Download Copyrighted Material

2996R_ch16_535-563
5/1/01
12:26 PM
Page 535
CHAPTER 16
TOXIC RESPONSES OF THE
NERVOUS SYSTEM
Douglas C. Anthony, Thomas J. Montine,
William M. Valentine, and Doyle G. Graham
Environmental Factors Relevant to Neurodegenerative
Diseases
Axonopathies
Gamma-Diketones
Carbon Disulfide
IDPN
Acrylamide
Organophosphorus Esters
Pyridinethione
Microtubule-Associated Neurotoxicity
Myelinopathies
Hexachlorophene
Tellurium
Lead
Neurotransmission-Associated Neurotoxicity
Nicotine
Cocaine and Amphetamines
Excitatory Amino Acids
Co
py
rig
hte
dM
ate
ria
l
OVERVIEW OF THE NERVOUS SYSTEM
Blood-Brain Barrier
Energy Requirements
Axonal Transport
Axonal Degeneration
Myelin Formation and Maintenance
Neurotransmission
Development of the Nervous System
FUNCTIONAL MANIFESTATIONS OF
NEUROTOXICITY
MECHANISMS OF NEUROTOXICITY
Neuronopathies
Doxorubicin
Methyl Mercury
Trimethyltin
Dopamine, 6-Hydroxydopamine, and
Catecholamine Toxicity
MPTP
duced to several generalities that allow a basic understanding of
the actions of neurotoxicants. These general principles include (1)
the privileged status of the NS with the maintenance of a biochemical barrier between the brain and the blood, (2) the importance of the high energy requirements of the brain, (3) the spatial
extensions of the NS as long cellular processes and the requirements of cells with such a complex geometry, (4) the maintenance
of an environment rich in lipids, and (5) the transmission of information across extracellular space at the synapse. Each of these
features of the NS carries with it specialized metabolic requirements and unique vulnerabilities to toxic compounds.
OVERVIEW OF THE NERVOUS
SYSTEM
Neurotoxicants and toxins have been extensively studied, both because of their toxic effects on humans and because of their utility
in the study of the nervous system (NS). Many insights into the
organization and function of the NS are based on observations derived from the action of neurotoxicants. The binding of exogenous
compounds to membranes has been the basis for the definition of
specific receptors within the brain; an understanding of the roles
of different cell types in the function of the NS has stemmed from
the selectivity of certain toxicants in injuring only certain cell types;
and important differences in basic metabolic requirements of different subpopulations of neurons have been inferred from the effects of toxicants.
It is estimated that millions of people worldwide are exposed
to known neurotoxicants each year, a fact underscored by repeated
outbreaks of neurologic disease (Federal Register, 1994). An even
larger potential problem is the incomplete information on many
compounds that may have neurotoxic effects. Unknown is the
extent to which neurologic disability may be related to chronic lowlevel exposures, nor do we understand the overall impact of environmental contaminants on brain function.
In order to study neurotoxicologic diseases, one must understand some of the anatomy, physiology, development, and regenerative capacity of the NS. These complex functions can be re-
Blood-Brain Barrier
The NS is protected from the adverse effects of many potential toxicants by an anatomic barrier. In 1885, Ehrlich, while studying the
distribution of dyes in the body, noticed that although other tissues
became stained, the brain and spinal cord did not develop the color
of the dyes. This observation pointed to the existence of an interface between the blood and the brain, or a “blood-brain barrier.”
Most of the brain, spinal cord, retina, and peripheral NS maintain
this barrier with the blood, with a selectivity similar to the interface between cells and extracellular space. The principal basis of
the blood-brain barrier is thought to be specialized endothelial cells
in the brain’s microvasculature, aided, at least in part, by interactions with glia (Kniesel and Wolburg, 2000).
535
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
536
5/26/01
8:27 AM
Page 536
UNIT 4 TARGET ORGAN TOXICITY
Energy Requirements
Neurons and cardiac myocytes are highly dependent upon aerobic
metabolism. These cells share the property of conduction of electrical impulses, and their dependence on aerobic respiration emphasizes the high metabolic demand associated with the maintenance and repetitive reinstitution of ion gradients. Membrane
depolarizations and repolarizations occur with such frequency that
these cells must be able to produce large quantities of high-energy
phosphates even in a resting state. That the energy requirements of
the brain are related to membrane depolarizations is supported by
the fact that hyperactivity, as in epileptic foci, increases the energy
requirements by as much as five times (Plum and Posner, 1985).
The dependence on a continual source of energy, in the absence of
energy reserves, places the neuron in a vulnerable position. To meet
these high energy requirements, the brain utilizes aerobic glycolysis and, therefore, is extremely sensitive to even brief interruptions in the supply of oxygen or glucose.
The systemic exposure to toxicants that inhibit aerobic respiration, such as cyanide, or to conditions that produce hypoxia, such
as carbon monoxide (CO) poisoning, leads to the earliest signs of
dysfunction in the myocardium and neurons. Damage to the NS
under these conditions is a combination of direct toxic effects on
neurons and secondary damage from systemic hypoxia or ischemia.
For example, acute CO poisoning damages those structures in the
central nervous system (CNS) that are most vulnerable to hypoxia:
the neurons in specific regions of the basal ganglia and hippocampus, certain layers of the cerebral cortex, and the cerebellar
Purkinje cells. Experiments utilizing several different laboratory
animal species have shown that systemic hypotension is the best
predictor of these lesions following CO poisoning; however, CO
poisoning also may produce white matter damage, and this
Co
py
rig
hte
dM
ate
ria
l
Among the unique properties of endothelial cells in the NS is
the presence of tight junctions between cells (Kniesel and Wolburg,
2000; Rubin and Staddon, 1999), compared to the 4-nm gaps between endothelial cells outside the NS. To gain entry to the NS,
molecules must pass through the cell membranes of endothelial
cells of the brain rather than between endothelial cells, as they do
in other tissues (Fig. 16-1). The blood-brain barrier also contains
xenobiotic transporters, such as the multidrug-resistant protein,
which transports some xenobiotics that have diffused through endothelial cells back into the blood. Aside from molecules that are
actively transported in the brain, the penetration of toxicants or
their metabolites into the NS is largely related to their lipid solubility and to their ability to pass through the plasma membranes of
the cells forming the barrier (Pardridge, 1999; Stewart, 2000).
There are important exceptions to this general rule. In the mature
NS, the spinal and autonomic ganglia as well as a small number
of other sites within the brain, called circumventricular organs, do
not contain specialized endothelial tight junctions and are not protected by blood-tissue barriers. This discontinuity of the barrier allows entry of the anticancer drug doxorubicin into the sensory ganglia and forms the basis for the selective neurotoxicity of this
compound to ganglionic neurons (Spencer, 2000). The blood-brain
barrier is incompletely developed at birth and even less so in premature infants. This predisposes the premature infant to brain injury by toxins, such as unconjugated bilirubin, that later in life are
excluded from the NS (Lucey et al., 1964).
In addition to this interface with blood, the brain, spinal cord,
and peripheral nerves are also completely covered with a continuous lining of specialized cells that limits the entry of molecules
from adjacent tissue. In the brain and spinal cord, this surface is
the meningeal surface; in peripheral nerves, each fascicle of nerve
is surrounded by perineurial cells.
Figure 16-1. Schematic diagram of the blood-brain barrier.
Systemic capillaries are depicted with intercellular gaps, or fenestrations, which permit the passage of molecules incapable of crossing the endothelial cell. There is also more abundant pinocytosis in systemic capillaries, in addition to the transcellular passage of lipid soluble compounds. In brain capillaries, tight junctions between endothelial cells and the lack of pinocytosis limit transport to compounds with active transport mechanisms
or those which pass through cellular membranes by virtue of their lipid solubility.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/26/01
9:01 AM
Page 537
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
intracellular materials over great distances. Although the length of
neurons may exceed 200,000 times the dimensions of most other
cells, the cellular volume has not undergone a similar increase due
to the unique attribute of very fine cylindrical extensions of the cell
to span the long distances. In the form of long delicate axons, the
neuron spans large distances but maintains less cytoplasmic volume and cell surface. Even so, the volume of the axon is much
greater than the volume of the cell body. If one considers the lower
motor neuron in humans, the cell body is located in the spinal cord
and the axon extends to the site of innervation of a muscle at a distant location. In spite of the smaller diameter of the axon, the
tremendous distances traversed by the axon translate to an axonal
volume that is hundreds of times greater than that of the cell body
itself (Schwartz, 1991). This places a great burden on the neuron
to provide protein synthetic machinery for such a cytoplasmic volume. The cellular machinery is readily visible in large neurons
through the light microscope as the Nissl substance, which is
formed by clusters of ribosomal complexes for the synthesis of proteins (Parent, 1996). That this is a reflection of an unusual protein
synthetic burden may be surmised from the fact that neurons are
the only cell type with such a Nissl substance.
In addition to the increased burden of protein synthesis, the
neuron is dependent on the ability to distribute materials over the
distances encompassed by its processes. While analogous systems
exist in all cell types and are referred to as cytoplasmic streaming,
in the NS this process occurs over much greater distances and is
referred to as axonal transport. Protein synthesis occurs in the cell
body, and the protein products are then transported to the appropriate site through the process of axonal transport. The assembly
of the cytoskeleton at tremendous distances from their site of synthesis in the cell body represents a formidable challenge (Nixon,
1998). Through studies of the movement of radiolabeled amino
acid precursors, several major components of axonal transport are
known (Grafstein, 1995). The fastest component is referred to as
fast axonal transport and carries a large number of proteins from
their site of synthesis in the cell body into the axon. Many of these
proteins are associated with vesicles (Grafstein, 1995) and migrate
through the axon at a rate of 400 mm/day (Fig. 16-2). This process
has been known for some time to be dependent on ATP, but it was
Co
py
rig
hte
dM
ate
ria
l
leukoencephalopathy may result from a primary effect of CO in
the CNS (Penny, 1990). As in the case of acute CO intoxication,
survivors of cyanide poisoning may develop lesions in the CNS
that are characteristic of systemic hypoxic or ischemic injury, and
experiments in rats and monkeys have led to the conclusion that
global hypoperfusion, rather than direct histotoxicity, is the major
cause of CNS damage (Auer and Benveniste, 1997). 3-Nitropropionic acid (3-NP), a naturally occurring mycotoxin, is an irreversible
inhibitor of succinate dehydrogenase that produces adenosine
triphosphate (ATP) depletion in cerebral cortical explants and is
associated with motor disorders in livestock and humans that have
ingested contaminated food (Ludolf et al., 1991, 1992). Some investigators removed the complication of systemic toxicity by directly injecting 3-NP into specific regions of the brain. They have
observed neuron degeneration mediated in part by excitotoxic
mechanisms (Brouillet et al., 1993). These examples demonstrate
the exquisite sensitivity of neurons to energy depletion and also
underscore the complex relationships between direct neurotoxicity
and the effects of systemic toxicity on the NS.
Axonal Transport
Some forms of intercellular communication are conducted through
the vascular system as hormones, which transmit information to
remote sites through the bloodstream. Some information, however,
is too vital to be conducted in such a diffuse and slow manner, and
the NS can be envisioned as a remedy to the obstacle of space in
intercellular communication. Impulses are conducted over great
distances at rapid speed and provide information about the environment to the organism in a coordinated manner that allows an
organized response to be carried out at a specific site. However,
the intricate organization of such a complex network places an unparalleled demand on the cells of the NS. Single cells, rather than
being spherical and a few micrometers in diameter, are elongated
and may extend over a meter in length!
The anatomy of such a complex cellular network creates features of metabolism and cellular geometry that are peculiar to the
NS. The two immediate demands placed on the neuron are the
maintenance of a much larger cellular volume and the transport of
537
Figure 16-2. Schematic diagram of axonal transport.
Fast axonal transport is depicted as spherical vesicles moving along microtubules with intervening microtubuleassociated motors. The slow component A (SCa) represents the movement of the cytoskeleton, composed of
neurofilaments and microtubules. Slow component b (SCb) moves at a faster rate than SCa and includes soluble proteins, which are apparently moving between the more slowly moving cytoskeleton.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
538
5/1/01
12:26 PM
Page 538
UNIT 4 TARGET ORGAN TOXICITY
as well and undergoes a process of chromatolysis, a response of
the cell body to degeneration of the axon.
Axonal Degeneration Current concepts of axonal degeneration
were initially derived from the transection of nerve, first reported
by Augustus Waller over a hundred years ago. Accordingly, the recognized sequence of events that occur in the distal stump of an
axon following transection are referred to as Wallerian degeneration. Because the axonal degeneration associated with chemical
agents and some disease states is thought to occur through a similar sequence of events, it is often referred to as Wallerian-like
axonal degeneration.
Following axotomy, there is degeneration of the distal nerve
stump, followed by generation of a microenvironment supportive
of regeneration. This process proceeds through a sequence of
changes involving the distal axon, ensheathing glial cells and the
blood nerve barrier. Initially there is a period during which the distal stump survives and maintains relatively normal structural, transport, and conduction properties. The duration of survival is proportional to the length of the axonal stump (Chaudry and Cornblath,
1992), and this relationship appears to be maintained across
species. An exception has been noted in the C57/BL6/01a mouse,
in which transected nerve fibers function electrically for 14 to 28
days (Lunn et al., 1989). Although the underlying reason for slow
degeneration in this mutant is unknown, the trait is transmitted by
a dominant gene on chromosome 4 (Lyon et al., 1993) and is an
intrinsic property of the neuron that does not involve macrophages
or Schwann cells (Glass et al., 1993). Terminating the period of
survival is an active proteolysis that digests the axolemma and axoplasm, leaving only a myelin sheath surrounding a swollen degenerate axon (Fig. 16-3). Digestion of the axon appears to be an
all-or-none event effected through endogenous proteases (Schaefler
and Zimmerman, 1984) that appear to be activated through increased levels of intracellular free Ca2 (George et al., 1995). Although it is established that degeneration of the most terminal portion of the axon occurs first, whether degeneration of the remainder
of the stump occurs from proximal to distal, distal to proximal, or
simultaneously along its entire length remains a matter of debate.
The active proteolysis phase occurs so rapidly in mammals that it
has been difficult to define a spatial distribution.
Schwann cells respond to loss of axons by decreasing synthesis of myelin lipids, down-regulating genes encoding myelin
proteins, and dedifferentiating to a premyelinating mitotic Schwann
cell phenotype (Stoll and Muller, 1999). The proliferating Schwann
cells align along the original basal lamina, which creates a tubular
structure referred to as a band of Bungner. In addition to providing physical guidance for regenerating axons, these tubes provide
trophic support from nerve growth factor, brain-derived nerve
growth factor, insulin-like growth factor, and corresponding receptors produced by the associated Schwann cells. Resident
macrophages distributed along the endothelium within the endoneurium and the denervated Schwann cells assist in clearing
myelin debris, but the recruitment of hematogenous macrophages
accounts for the removal of the majority of myelin. Infiltrating
macrophages express complement receptor 3, and the presence of
complement 3 on the surface of degenerating myelin sheaths facilitates opsonization. In contrast to the proteolysis of the axon,
processing of myelin breakdown products proceeds in an established proximal-to-distal progression. Another essential role of recruited circulating macrophages is the secretion of interleukin-1,
Co
py
rig
hte
dM
ate
ria
l
not until the description of a microtubule-associated ATPase activity that there rapidly emerged the concept of microtubuleassociated motor proteins. These proteins, kinesin and dynein being the prototypes of a class of microtubule-associated motors,
provide both the mechanochemical force in the form of a microtubule-associated ATPase and the interface between microtubules
as the track and vesicles as the cargo. Vesicles are transported rapidly in an anterograde direction by kinesin, and they are transported
in a retrograde direction by dynein (Schnapp and Reese, 1989).
While this mechanism of cytoplasmic transport toward the cell periphery and back toward the nucleus appears to be a general feature of cells, the process is amplified within the NS by the distances encompassed by the axonal extensions of neurons. In the
axon, multiple waves of transport can be detected in the fast component of axonal transport (Mulugeta et al., 2000).
The transport of some organelles, including mitochondria,
constitutes an intermediate component of axonal transport, moving at 50 mm/day (Grafstein, 1995). As with the fast component,
the function is apparently the continuous replacement of organelles
within the axon. The slowest component of axonal transport
represents the movement of the cytoskeleton itself, rather than
the movement of enzymes or organelles through the cytosol
(Fig. 16-2). The cytoskeleton is composed of structural elements,
including microtubules formed by the association of tubulin subunits and neurofilaments formed by the association of three neurofilament protein subunits. Dynamic exchange of subunits of the
filamentous structure has now been observed with high-resolution
microscopy of living cells, indicating that stationary filamentous
structures exchange subunits that move rapidly once dissociated
(Wang et al., 2000). Each of the elements of the cytoskeleton moves
along the length of the axon at a specific rate. Overall, slow component A (SCa), so named to distinguish this wave of movement
from another slow component of axonal transport, slow component
B (SCb) (Hoffman and Lasek, 1975), is composed of the movement of the axonal cytoskelton in an anterograde direction.
Neurofilaments and microtubules move at a rate of approximately 1 mm/day and make up the majority of SCa, the slowestmoving component of axonal transport. Subunit structures appear
to migrate and reassemble in a process that is dependent on nucleoside triphosphates, kinases, and phosphatases (Koehnle and
Brown, 1999; Nixon, 1998). Moving at only a slightly more rapid
rate of 2 to 4 mm/day is SCb, which is composed of many proteins (Grafstein, 1995). Included in SCb are several structural proteins, such as the component of microfilaments (actin) and several
microfilament-associated proteins (M2 protein and fodrin), as well
as clathrin and many soluble proteins.
This continual transport of proteins from the cell body through
the various components of forward-directed, or anterograde, axonal transport is the mechanism through which the neuron provides
the distal axon with its complement of functional and structural
proteins. Some vesicles are also moving in a retrograde direction
and undoubtedly provide the cell body with information concerning the status of the distal axon. The evidence for such a dynamic
interchange of materials and information stems not only from the
biochemical detection of these components of axonal transport but
also from the observations of the effects of terminating this interchange by severing the axon from its cell body. The result of transection of an axon is that the distal axon is destined to degenerate,
a process known as axonal degeneration which is unique to the NS.
The cell body of the neuron responds to the transection of the axon
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/26/01
8:29 AM
Page 539
539
Co
py
rig
hte
dM
ate
ria
l
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
Figure 16-3. Schematic diagram of axonal degeneration.
Following axotomy, or chemical injury of an axon, the distal portion of the axon undergoes a process of axonal
degeneration. Initial stages of axonal swelling are followed by fragmentation of the distal axon and phagocytosis by resident Schwann cells and an influx of macrophages, which are largely derived from the circulation.
which is responsible for stimulating production of nerve growth
factor by Schwann cells.
Investigations have shown that degeneration of the distal axonal stump after transection is an active, synchronized process that
can be delayed experimentally through decreasing temperature,
preventing the entry of extracellular Ca2 or inhibiting proteolysis by calpain II (George et al., 1995). Accompanying events in
glial cells and macrophages direct and facilitate the sprouting neurite originating from the surviving proximal axon that also undergoes changes in protein expression resembling a less differentiated
state. The facilitation of regeneration in the peripheral nervous system by Schwann cells distinguishes it from the central nervous system (CNS), in which oligodendrocytes secrete inhibitory factors
that impede neurite outgrowth. Eventually, though, even in the peripheral nervous system (PNS), if axonal contact is not restored,
Schwann cell numbers will decrease, bands of Bungner will disappear, and increased fibroblast collagen production will render regeneration increasingly unlikely.
These dynamic relationships between the neuronal cell body
and its axon are important in understanding the basic pathological
responses to axonal and neuronal injuries caused by neurotoxicants.
When the neuronal cell body has been lethally injured, it degen-
erates, along with all of its cellular processes. This process is a
neuronopathy and is characterized by the loss of the cell body and
all of its processes, with no potential for regeneration. However,
when the injury is at the level of the axon, the axon may degenerate while the neuronal cell body continues to survive, a condition
known as an “axonopathy” (Fig. 16-4). In this setting, there is a
potential for regeneration and recovery from the toxic injury as the
axonal stump sprouts and regenerates. Since axonal transport is the
process by which the neuron supplies proteins to the distal portions of the axon, axonal transport systems have become of major
interest in attempts to understand the toxic degeneration of axons.
Myelin Formation and Maintenance
Myelin is formed in the CNS by oligodendrocytes and in the PNS
by Schwann cells. Both of these cell types form concentric layers
of lipid-rich myelin by the progressive wrapping of their
cytoplasmic processes around the axon in successive loops (Fig.
16-5). Ultimately, these cells exclude cytoplasm from the inner surface of their membranes to form the major dense line of myelin
(Quarles et al., 1997; Monuki and Lemke, 1995; Parent, 1996). In
a similar process, the extracellular space is reduced on the extra-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
540
5/26/01
8:33 AM
Page 540
UNIT 4 TARGET ORGAN TOXICITY
Co
py
rig
hte
dM
ate
ria
l
2996R_ch16_535-563
Figure 16-4. Patterns of neurotoxic injury.
A neuronopathy results from the death of the entire neuron. Astrocytes often proliferate in response to the neuronal loss, creating both neuronal loss and gliosis. When the axon is the primary site of injury, the axon degenerates, while the surviving neuron shows only chromatolysis with margination of its Nissl substance and nucleus to the cell periphery. This condition is termed an axonopathy. Myelinopathies result from disruption of
myelin or from selective injury to the myelinating cells. To prevent cross-talk between adjacent axons, myelinating cells divide and cover the denuded axon rapidly; however, the process of remyelination is much less effective in the CNS than in the PNS. Some compounds do not lead to cell death but exert their toxic effects by
interrupting the process of neurotransmission, either through blocking excitation or by excessive stimulation.
cellular surface of the bilayers, and the lipid membranes stack together, separated only by a proteinaceous intraperiod line existing
between successive layers.
The formation and maintenance of myelin requires metabolic
and structural proteins that are unique to the NS. Myelin basic
protein, an integral protein of CNS myelin, is closely associated
with the intracellular space (at the major dense line of myelin)
(Quarles et al., 1997; Monuki and Lemke, 1995), and an analogous
protein, P1 protein, is located in the PNS. On the extracellular surface of the lipid bilayers is the CNS protein, proteolipid protein,
at the intraperiod line of myelin. Mutation of this protein in several species, including humans, or overexpression of the wild-type
gene in transgenic mice, results in disorders in which myelin of
the CNS does not form normally (Pham-Dinh et al., 1991; Readhead et al., 1994).
There are a variety of hereditary disorders in which myelin is
either poorly formed from the outset or is not maintained after its
formation. In addition to mutation of proteolipid protein, there are
a variety of inherited abnormalities of myelin proteins and myelinspecific lipid catabolism. These genetic defects have provided some
insight into the special processes required to maintain the lipidrich environment of myelin. It is now known that the maintenance
of myelin is dependent on a number of membrane-associated proteins and on metabolism of specific lipids present in myelin bi-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
6/6/01
5:11 PM
Page 541
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
541
Development of the Nervous System
Co
py
rig
hte
dM
ate
ria
l
Replication, migration, differentiation, myelination, and synapse
formation are the basic processes that underlie development of the
NS. Both neuronal and glial precursors replicate in a discrete zone
near the inner surface of the neural tube (Fig. 16-6). This germinal mantle, a collection of cells near the ventricular system, gives
rise to successive waves of neurons, which migrate toward the outer
surface of the brain to form the cerebral cortex, as well as other
neurons, supportive astrocytes, and myelinating oligodendrocytes.
Each wave of cells migrates from the germinal mantle in a precisely ordered sequence both in utero and in early postnatal life.
Myelination begins in utero and continues through childhood
(Kinney and Armstrong, 1997). Synaptic connectivity, the basis of
neurologic function, is a dynamic process throughout life.
Development of the brain during childhood provides a certain
resilience toward injuries. Much of this is due to the fact that the
younger brain has greater plasticity, an ability of one portion of the
NS to assume the function of an injured area. The brain of a child
may compensate partially for an injury that would result in much
greater disability in an adult (Goldberger and Murray, 1985). This
plasticity of the immature NS appears to derive from the ability of
Figure 16-5. Schematic diagram of myelination.
Myelination begins when a myelinating cell encircles an axon, either
Schwann cells in the peripheral nervous system or oligodendrocytes in the
central nervous system. Simple enclosure of the axon persists in unmyelinated axons. Myelin formation proceeds by a progressive wrapping of multiple layers of the myelinating cell around the axon, with extrusion of the
cytoplasm and extracellular space to bring the lipid bilayers into close proximity. The intracellular space is compressed to form the major dense line
of myelin, and the extracellular space is compressed to form the intraperiod line.
Germinal
Matrix
Replication
Central
Canal
layers. In the context of toxic exposures, it is easy to imagine how
some toxic compounds interfere with this complex process of the
maintenance of myelin and result in the toxic “myelinopathies”
(Fig. 16-4). In general, the loss of myelin, with the preservation of
axons is referred to as demyelination.
Migration
Cortical
Plate
Neural Tube
Neurotransmission
Convolution
Intercellular communication is achieved in the NS through the
synapse. Neurotransmitters released from one axon act as the first
messenger. Binding of the transmitter to the postsynaptic receptor
is followed by modulation of an ion channel or activation of a second messenger system, leading to changes in the responding cell.
In the case of neuromuscular transmission, acetylcholine crosses
the synaptic cleft to bind the cholinergic receptor of the myocyte
and leads to muscle contraction.
The process of neurotransmission is targeted by a variety of
therapeutic drugs and is a major component of the science of neuropharmacology. In addition, there are a variety of toxic compounds
that interact directly with the process of neurotransmission, hence
forming the basis of neurotransmitter-associated toxicity. To a certain extent, many of the toxic effects associated with neurotransmitters is related to the dose. While a desirable effect may occur,
with some agonists or antagonists acting at a neurotransmitter receptor site, excessive effect may result in neurotoxicity. The therapeutic index, in general, is a measure of the margin between the
desirable and toxic effects of a compound. Thus, the very processes
targeted by many clinical neuropharmacologic strategies and drug
designs are also the targets of certain neurotoxic compounds.
Germinal
Matrix
Cerebral Ventricles
Figure 16-6. Development of the central nervous system.
Initially a tube of committed neuroepithelial cells around a central lumen
(the neural tube), the central nervous system develops by replication of cells
within the periventricular germinal matrix and migration of waves of neurons toward the surface. The basic tube structure persists in the spinal cord
with its central canal. However, in the forebrain, the tube becomes extensively convoluted to form the gyrations of the brain.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
542
5/1/01
12:26 PM
Page 542
UNIT 4 TARGET ORGAN TOXICITY
rotoxic compounds reliably. Ultimately, neurotoxicants identified
by behavioral methods are evaluated at a cellular and molecular
level to provide an understanding of the events in the NS that cause
the neurologic dysfunction detected by observational tests.
MECHANISMS OF
NEUROTOXICITY
Efforts to understand the mechanism of action of individual neurotoxic compounds have begun with the identification of the cellular target. In the nervous system, this has most often been one of
four targets: the neuron, the axon, the myelinating cell, or the neurotransmitter system. As a result, neurotoxic compounds may be
identified which cause neuronopathies, axonopathies, myelinopathies, or neurotransmitter-associated toxicity (Fig. 16-4). This is
the classification system that is utilized here to organize the discussion of neurotoxic compounds and their mechanisms of action.
Co
py
rig
hte
dM
ate
ria
l
dendrites to arborize and form new synapses. It is both curious and
tragic that this capacity wanes with age.
This regenerative ability notwithstanding, the immature NS is
especially vulnerable to certain agents. Ethanol exposure during
pregnancy can result in abnormalities in the fetus, including abnormal neuronal migration, abnormal facial development, and
diffuse abnormalities in the development of neuronal processes,
especially the dendritic spines (Stoltenburg-Didinger and Spohre,
1983). While the exposure may be of little consequence to the
mother, it can be devastating to the fetus. There is an effect on
NMDA glutamate receptors and excessive activation of GABA receptors, with induction of apoptosis throughout the brain (Ikonomidou et al., 2000). The clinical result of fetal alcohol exposure is
often mental retardation, with malformations of the brain and delayed myelination of white matter (Riikonen et al., 1999). Although
there remains a great deal of uncertainty concerning the molecular basis of this developmental aberration, it occurs in a variety of
experimental animals, and it appears that acetaldehyde, a product
of ethanol catabolism, can produce migration defects in developing animals similar to those that occur in the fetal alcohol syndrome (O’Shea and Kaufman, 1979).
FUNCTIONAL MANIFESTATIONS
OF NEUROTOXICITY
A variety of methods are available to investigate the deleterious effects of neurotoxicants. A complete biochemical or molecular
mechanism for all toxicants is the ultimate goal of neurotoxicology, and it is from this perspective that the remainder of this chapter presents specific neurotoxic agents. One hastens to note that a
vast ignorance lies between our current knowledge and this objective. The foremost priority is the identification of potential neurotoxicants. It is here that behavioral methods continue to make great
achievements. In most instances, mechanistic data have accrued
following functional assessment of exposed populations.
The strength of functional assessment has been exploited by
many investigators and regulatory agencies that now employ functional test batteries as a means for screening potentially neurotoxic
compounds (Tilson, 1993). A group or “battery” of behavioral tests
is typically performed to evaluate a variety of neurologic functions,
and its validity has been established with collaborative intergroup
measures (Moser et al., 1997a). These functional observational batteries (FOBs) have the advantage over biochemical and pathologic
measures that they permit evaluation of a single animal over longitudinal studies to determine the onset, progression, duration, and
reversibility of a neurotoxic injury. In addition, repeated exposures
may lead to tolerance in behavioral measures. Tilson has proposed
two distinct tiers of functional testing of neurotoxicants: a first tier
in which FOBs or motor activity tests may be used to identify the
presence of a neurotoxic substance, and a second tier that involves
characterization of the effects of the compound on sensory, motor,
autonomic, and cognitive functions (Tilson, 1993). The second tier
is critical, since it is in this phase that the validity of behavioral
tests is established, and behavioral changes are correlated with
physiologic, biochemical, and pathologic identification of neurotoxic injury (Becking et al., 1993). Problems exist in the crossspecies extrapolation of behavioral abnormalities from experimental animals to humans (Winneke, 1992). Nonetheless, comparisons
of defined protocols of FOBs with limited numbers of compounds
(Moser et al., 1997b,c) suggest that these methods can identify neu-
Neuronopathies
Certain toxicants are specific for neurons, or sometimes a particular group of neurons, resulting in their injury or, when intoxication is severe enough, their death. The loss of a neuron is irreversible and includes degeneration of all of its cytoplasmic
extensions, dendrites and axons, and of the myelin ensheathing the
axon (Fig. 16-4). Although the neuron is similar to other cell types
in many respects, some features of the neuron are unique, placing
it at risk for the action of cellular toxicants. Some of the unique
features of the neuron include a high metabolic rate, a long cellular process that is supported by the cell body, and an excitable
membrane that is rapidly depolarized and repolarized. Because
many neurotoxic compounds act at the site of the cell body, when
massive loss of axons and myelin are discovered in the PNS or
CNS, the first question is whether the neuronal cell bodies themselves have been destroyed.
Although a large number of compounds are known to result
in toxic neuronopathies (Table 16-1), all of these toxicants share
certain features. Each toxic condition is the result of a cellular toxicant that has a predilection for neurons, most likely due to one of
the neuron’s peculiar vulnerabilities. The initial injury to neurons
is followed by apoptosis or necrosis, leading to permanent loss of
the neuron. These agents tend to be diffuse in their action, although
they may show some selectivity in the degree of injury of different neuronal subpopulations or at times an exquisite selectivity for
such a subpopulation. The expression of these cellular events is often a diffuse encephalopathy, with global dysfunctions; however,
the symptomatology reflects the injury to the brain, so neurotoxicants that are selective in their action and affect only a subpopulation of neurons may lead to interruption of only a particular functionality.
Doxorubicin Although it is the cardiac toxicity that limits the
quantity of doxorubicin (Adriamycin) that can be given to cancer
patients, doxorubicin also injures neurons in the PNS, specifically
those of the dorsal root ganglia and autonomic ganglia (Spencer,
2000). This selective vulnerability of peripheral ganglion cells is
particularly dramatic in experimental animals, where it has been
well documented. Doxorubicin is an anthracycline antibiotic derivative whose antineoplastic properties derive from its ability to
intercalate in double-stranded DNA, interfering with transcription.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
NEUROTOXICANT
Microcephaly, cerebral malformations
Brain swelling, hemorrhages (acute), axonal loss in PNS (humans)
b
a–c
Degeneration of striatum, globus pallidus
Insufficient data in humans (may affect spinal tracts; cerebellum)
Necrosis of putamen, degeneration of retinal ganglion cells
Developmental abnormalities of fetal brain (rats)
a, b
a–c
b, c
d
Visual and speech impairment; peripheral neuropathy
Ataxia, constriction of visula fields, paresthesias (adult)
Psychomotor retardation (fetal exposure)
Parkinsonism, dystonia (acute exposure)
Early onset parkinsonism (late effect of acute exposure)
Insufficient data
Neuronal degeneration, visual cortex, cerebellum, ganglia
Spongy disruption, cortex and cerebellum
Neuronal degeneration in substantia nigra
Neuronal degeneration in substantia nigra
c
a–c
b, c
b, c
b, c
Seizures, delayed dystonia/grimacing
Nystagmus, ataxia, dizziness
Necrosis in basal ganglia
Degeneration of Purkinje cells (cerebellum)
b, c
b, c
Constriction of visual fields
Hearing loss
Vacuolization of retinal ganglion cells
Degeneration of inner ear (organ of Corti)
Emotional disturbances, ataxia, peripheral neuropathy
Tremors, hyperexcitability (experimental animals)
Brain swelling (acute), axonal degeneration in PNS
Loss of hippocampal neurons, amygdala pyriform cortex
Arsenic
Not reported in humans; hind limb paralysis
(experimental animals)
Encephalopathy (acute), peripheral neuropathy (chronic)
Azide
Bismuth
Carbon monoxide
Insufficient data (humans); convulsions, ataxia (primates)
Emotional disturbances, encephalopathy, myoclonus
Encephalopathy, delayed parkinsonism/dystonia
Carbon tetrachloride
Chloramphenicol
Cyanide
Encephalopathy (probably secondary to liver failure)
Optic neuritis, peripheral neuropathy
Coma, convulsions, rapid death; delayed
parkinsonism/dystonia
Insufficient data (humans); progressive ataxia
(experimental animals)
Mental retardation, hearing deficits (prenatal exposure)
Encephalopathy (acute), learning deficits (children),
neuropathy with demyelination (rats)
Emotional disturbances, parkinsonism/dystonia
Emotional disturbances, tremor, fatigue
Headache, visual loss or blindness, coma (severe)
Microcephaly (rats)
Manganese
Mercury, inorganic
Methanol
Methylazoxymethanol
acetate
Methyl bromide
Methyl mercury (organic
mercury)
1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine
(MPTP)
3-Nitropropionic acid
Phenytoin (diphenylhydantoin; Dilantin)
Quinine
Streptomycin
(aminoglycosides)
Thallium
Trimethyltin
Co
py
rig
hte
dM
ate
ria
l
6-Amino-nicotinamide
Chang LW, Dyer RS, eds: Handbook of Neurotoxicology. New York: Marcel Dekker, 1995.
Graham DI, Lantos PL, eds: Greenfield’s Neuropathology, 6th ed. New York: Arnold, 1997.
c
Spencer PS, Schaumburg HH, eds: Experimental and Clinical Neurotoxicology, 2d ed. New York: Oxford University Press, 2000.
d
Abou-Donia MB, ed: Neurotoxicology. Boca Raton, FL: CRC Press, 1993.
b
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
b, c
b, c
b, c
c
c
c
b, c
b, c
c
c
b, c
b
Page 543
a–c
12:26 PM
Spongiosis cortex, neurofibrillary aggregates, degenerative changes in
cortex
Spongy (vacuolar) degeneration in spinal cord, brainstem, cerebellum;
axonal degeneration of the peripheral nervous system (PNS)
Brain swelling and hemorrhage (acute), axonal degeneration in PNS
(chronic)
Neuronal loss in cerebellum and cortex
Neuronal loss, basal ganglia and Purkinje cells of cerebellum
Neuronal loss in cortex, necrosis of globus pallidus, focal demyelination;
blocks oxygen binding site of hemoglobin and iron-binding sites of brain
Enlarged astrocytes in striatum, globus pallidus
Neuronal loss (retina), axonal degeneration (PNS)
Neuronal degeneration, cerebellum and globus pallidus; focal
demyelination; blocks cytochrome oxidase/ATP production
Degeneration of dorsal root ganglion cells, axonal degeneration (PNS)
5/1/01
REFERENCE
Dementia, encephalopathy (humans), learning deficits
Ethanol
Lead
543
CELLULAR BASIS OF NEUROTOXICITY
Aluminum
Doxorubicin
a
NEUROLOGIC FINDINGS
2996R_ch16_535-563
Table 16-1
Compounds Associated with Neuronal Injury (Neuronopathies)
2996R_ch16_535-563
544
5/1/01
12:26 PM
Page 544
UNIT 4 TARGET ORGAN TOXICITY
syndrome in humans and similar behavioral changes in primates
(Besser et al., 1987; Reuhl et al., 1985). Trimethyltin gains access
to the nervous system where, by an undefined mechanism, it leads
to diffuse neuronal injury. Many neurons of the brain begin to accumulate cytoplasmic bodies composed of Golgi-like structures,
followed by cellular swelling and necrosis (Bouldin et al., 1981).
The hippocampus is particularly vulnerable to this process. Following acute intoxication, the cells of the fascia dentata degenerate; with chronic intoxication, the cells of the corpus ammonis are
lost. Ganglion cells and hair cells of the cochlea are similarly sensitive (Liu and Fechter, 1996). Several hypotheses seek the mechanism of trimethyltin neurotoxicity, including energy deprivation
and excitotoxic damage. The role of stannin, a protein present in
trimethyltin-sensitive neurons (Toggas et al., 1992), remains to be
established, though the gene has been sequenced and is highly conserved between species (Dejneka et al., 1998).
Co
py
rig
hte
dM
ate
ria
l
Because all neurons are dependent on the ability to transcribe DNA,
it is quite interesting that the neurotoxicity of doxorubicin is so
limited in its extent. The particular vulnerability of sensory and autonomic neurons appears to reflect the lack of protection of these
neurons by a blood-tissue barrier within ganglia. If the blood-brain
barrier is temporarily opened by the use of mannitol, the toxicity
of doxorubicin is expressed in a much more diffuse manner, with
injury of neurons in the cortex and subcortical nuclei of the brain
(Spencer, 2000).
Methyl Mercury The neuronal toxicity of organomercurial compounds, such as methyl mercury, was tragically revealed in large
numbers of poisonings in Japan and Iraq. The residents of Minamata Bay in Japan, whose diet was largely composed of fish from
the bay, were exposed to massive amounts of methyl mercury when
mercury-laden industrial effluent was rerouted into the bay (Kurland et al., 1960; Takeuchi et al., 1962). Methyl mercury injured
even more people in Iraq, with more than 400 deaths and 6000
people hospitalized. In this epidemic, as well as in several smaller
ones, the effects occurred after the consumption of grain that had
been dusted with methyl mercury as an inexpensive pesticide
(Bakir et al., 1973).
The clinical picture varies both with the severity of exposure
and the age of the individual at the time of exposure. In adults, the
most dramatic sites of injury are the neurons of the visual cortex
and the small internal granular cell neurons of the cerebellar cortex, whose massive degeneration results in blindness and marked
ataxia. In children, particularly those exposed to methyl mercury
in utero, the neuronal loss is widespread, and in settings of greatest exposure, it produces profound mental retardation and paralysis (Reuhl and Chang, 1979). Studies on primates exposed in utero
also have demonstrated abnormal social development (Burbacher
et al., 1990). Recent studies in rats show that the neurons that are
most sensitive to the toxic effects of methyl mercury are those that
reside in the dorsal root ganglia, perhaps again reflecting the vulnerability of neurons not shielded by blood-tissue barriers (Schionning et al., 1998).
The mechanism of methyl mercury toxicity has been the subject of intense investigation. However, it remains unknown whether
the ultimate toxicant is methyl mercury or the liberated mercuric
ion. While Hg2 is known to bind strongly to sulfhydryl groups,
it is not clear that MeHg results in cell death through sulfhydryl
binding. A variety of aberrations in cellular function have been
noted, including impaired glycolysis, nucleic acid biosynthesis,
aerobic respiration, protein synthesis (Cheung and Verity, 1985),
and neurotransmitter release (Atchison and Hare, 1994). In addition, there is evidence for enhanced oxidative injury (LeBel et al.,
1992) and altered calcium homeostasis (Marty and Atchison, 1997).
It seems likely that MeHg toxicity is mediated by numerous reactions and that no single critical target will be identified. As these
toxic events occur, the injured neurons eventually die. Exposure to
methyl mercury leads to widespread neuronal injury and subsequently to a diffuse encephalopathy. However, there is relative selectivity of the toxicant for some groups of neurons over others.
The distribution of neuronal injury does not appear to be related
to the tissue distribution of either methyl mercury or ionic mercury
but rather to particular vulnerabilities of these neurons.
Trimethyltin Organotins are used industrially as plasticizers, antifungal agents, or pesticides. Intoxication with trimethyltin has
been associated with a potentially irreversible limbic-cerebellar
Dopamine, 6-Hydroxydopamine, and Catecholamine Toxicity
The progressive loss of catecholaminergic neurons that occurs with
age has been postulated to derive from the toxicity of the oxidation products of catecholamines, especially dopamine, as well as
from the products of the partial reduction of oxygen. The oxidation of catecholamines by monoamine oxidase (MAO) yields H2O2,
a known cytotoxic metabolite. The metal ion–catalyzed autoxidation of catecholamines, especially dopamine, results in the production of catecholamine-derived quinones as well as superoxide
anion (O2–. ), H2O2 from O2–. dismutation, and the hydroxyl radical
(OH) from the Fenton reaction (Fig. 16-7) (Cohen and Heikkila,
1977; Graham et al., 1978). Cellular glutathione affords protection
from the flux of quinones, glutathione peroxidase from H2O2, and
superoxide dismutase from O2–. . Among the naturally occurring
catecholamines, dopamine is the most cytotoxic, because of both
its greater ease of autoxidation and the greater reactivity of its orthoquinone oxidation product (Graham, 1978). There is evidence
that the mercapturate of dopamine may play a major role in
dopaminergic neurodegeneration (Zhang et al., 2000b).
An analog of dopamine, 6-hydroxydopamine, is extremely potent in leading to a chemical sympathectomy. This compound fails
to cross the blood-brain barrier, so its site of action is limited to
the periphery after systemic administration. In addition, it does not
cross into peripheral nerves and gains access to nerves only at their
terminals. 6-Hydroxydopamine is actively transported into nerve
terminals, employing the uptake mechanism utilized by the structurally similar catecholamines in sympathetic terminals. The uptake of 6-hydroxydopamine results in an injury to sympathetic neurons due to oxidation of this catecholamine analog similar to what
occurs with dopamine (Fig. 16-7) (Graham, 1978). The result is
selective destruction of sympathetic innervation (Malmfors, 1971).
The sympathetic fibers degenerate, resulting in an uncompensated
parasympathetic tone, a slowing of the heart rate, and hypermotility of the gastrointestinal system. It is noteworthy that neurobiologists employ 6-hydroxydopamine to destroy specific groups of
catecholaminergic neurons. For example, stereotaxic injection of
6-hydroxydopamine into the caudate nucleus, which is rich in
dopaminergic synapses, leads to neurite degeneration; if it is injected into the substantia nigra, the cell bodies of the dopamine
neurons are destroyed (Marshall et al., 1983). The mechanism of
toxicity of 6-hydroxydopamine appears to derive from its autoxidation and production of reactive oxygen species (Storch et al.,
2000). Support for this mechanism is provided in the observation
that overexpression of either Cu,Zn-superoxide dismutase or glu-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/2/01
6:42 AM
Page 545
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
less affected by single exposures than the dopaminergic neurons.
Once inside neurons, MPP+ acts as a general mitochondrial toxin,
blocking respiration at complex I (DiMonte and Langston, 2000).
MPP+ may also lead to the production of activated oxygen species,
and MPPresults in the release of dopamine from vesicles to the
higher pH environment of the cytosol where it undergoes autoxidation (Lotharius and O’Malley, 2000). Mice deficient in either
Cu,Zn-superoxide dismutase or glutathione peroxidase show increased vulnerability to MPTP neurotoxicity (Zhang et al., 2000a),
while overexpression of manganese superoxide dismutase attenuates the toxicity (Klivenyi et al., 1998). Metallothionein-I and -II,
by contrast, do not play a role in protecting against MPTP (Rojas
and Klaassen, 1999). It should be noted that the general toxicity
of MPP+ itself is great when it is administered to animals, although
systemic exposure to MPP+ does not result in neurotoxicity because it does not cross the blood-brain barrier.
Although not identical, MPTP neurotoxicity and Parkinson’s
disease are strikingly similar. The symptomatology of each reflects
a disruption of the nigrostriatal pathway: masked facies, difficulties in initiating and terminating movements, resting “pill-rolling”
tremors, rigidity, and bradykinesias are all features of both conditions. Pathologically, there is an unusually selective degeneration
of neurons in the substantia nigra and depletion of striatal dopamine
in both diseases (Di Monte and Langston, 2000). However, PET
studies employing [(18)F]-fluorodopa show that while patients with
idiopathic Parkinson’s disease demonstrate greater loss of dopaminergic function in the putamen than the caudate nucleus, the loss
from these two nuclei was the same in patients who had taken
MPTP (Snow et al., 2000).
Co
py
rig
hte
dM
ate
ria
l
Figure 16-7. Catecholamine oxidation and activated oxygen species.
Both the enzyme-catalyzed oxidation of catecholamines, here illustrating
the action of monoamine oxidase (MAO) on norepinephrine, and the nonenzymatic oxidation of catecholamines generate activated oxygen species, including hydrogen peroxide and superoxide. There are intracellular enzymes
that handle the flux of superoxide (superoxide dismutase, SOD) and hydrogen peroxide (glutathione peroxidase, GSH Perox). The hydroxyl radical (OH) is a highly reactive molecule that may react with lipids, proteins,
and nucleic acids. Although originally thought to arise through the direct
reaction of peroxide (H2O2) and superoxide (O2.), it appears that the only
likely source of hydroxyl radical is through the metal-catalyzed Fenton reaction (with cycling of Fe3 and Fe2). In addition, the autoxidation of
catecholamines generates the semiquinone and the catecholamine-derived
quinone, which is a strong electrophile and reacts with available sulfhydryls.
tathione peroxidase in transgenic mice provides protection from
the toxicity of 6-hydroxydopamine (Bensadoun et al., 1998;
Asanuma et al., 1998).
MPTP Because of a chemist’s error, people who injected themselves with a meperidine derivative, or synthetic heroin, also received
a
contaminant,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP). Over hours to days, dozens of these patients developed the
signs and symptoms of irreversible Parkinson’s disease (Langston
and Irwin, 1986), some becoming almost immobile with rigidity. Autopsy studies have demonstrated marked degeneration of dopaminergic neurons in the substantia nigra, with degeneration continuing
many years after exposure (Langston et al., 1999).
It is surprising not only that a compound like MPTP is neurotoxic but also that MPTP is a substrate for the B isozyme of
monoamine oxidase (MAO-B). It appears that MPTP, an uncharged
species at physiologic pH, easily crosses the blood-brain barrier
and diffuses into cells, including astrocytes. The MAO-B of astrocytes catalyzes the two-electron oxidation to yield MPDP, the
corresponding dihydropyridinium ion. A further two-electron oxidation yields the pyridinium ion, MPP+ (Fig. 16-8). MPP+ enters
dopaminergic neurons of the substantia nigra via the dopamine uptake system, resulting in injury or death of the neuron. Noradrenergic neurons of the locus ceruleus are also vulnerable to repeated
exposures of MPTP (Langston and Irwin, 1986), although they are
545
Environmental Factors Relevant to Neurodegenerative
Diseases It has been observed that individuals exposed to insufficient MPTP to result in immediate parkinsonism have developed early
signs of the disease years later (Calne et al., 1985). This observation
presents the possibility that the onset of a neurotoxic problem may
follow toxic exposure by many years. It does not seem likely that an
early sublethal injury to dopaminergic neurons later becomes lethal.
Rather, smaller exposures to MPTP may cause a decrement in the
population of neurons within the substantia nigra. Such a loss would
most likely be silent, because the symptoms of Parkinson’s disease
do not develop until approximately 80 percent of the substantia nigra neurons are lost. These individuals with a diminished number of
neurons may be more vulnerable to further loss of dopaminergic neurons. The neurologic picture of Parkinson’s disease develops at an
earlier age than in unexposed individuals, as a further loss of catecholaminergic neurons occurs during the process of aging.
The relationship between MPTP intoxication and parkinsonism has stimulated investigations into the role that environmental
and occupational exposures may play in the pathogenesis of Parkinson’s disease. While several families with early-onset Parkinson’s
disease demonstrate autosomal dominant inheritance, with identification of candidate genes (Polymeropoulos et al., 1997; Agundez
et al., 1995; Kurth et al., 1993), twin studies indicate that environmental exposures play a more significant role than genetics in
the vast majority of Parkinson’s disease patients, particularly those
with late-onset disease (Tanner et al., 1999; Kuopio et al., 1999).
Epidemiologic studies implicate exposure to herbicides, pesticides,
and metals as risk factors for Parkinson’s disease (Gorell et al.,
1998, 1999; Liou et al., 1997). Several studies suggest that dithiocarbamates also play an important role (Miller, 1982; Ferraz et al.,
1988; Bachurin et al., 1996).
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
Page 546
UNIT 4 TARGET ORGAN TOXICITY
Co
py
rig
hte
dM
ate
ria
l
546
12:26 PM
Figure 16-8. Diagram of MPTP toxicity.
MPP, either formed elsewhere in the body following exposure to MPTP or injected directly into the blood, is
unable to cross the blood-brain barrier. In contrast, MPTP gains access and is oxidized in situ to MPDP and
MPP. The same transport system that carries dopamine into the dopaminergic neurons also transports the cytotoxic MPP.
Some studies suggest that cigarette smoking may have a protective effect against both Alzheimer’s disease and Parkinson’s disease, but alternative explanations have been offered (Riggs, 1992).
An epidemic of dialysis-related dementia with some pathologic resemblance to Alzheimer’s disease appears to have been related to
aluminum in the dialysate, and its removal has prevented further
instances of dialysis dementia. However, there is no substantial evidence to date that aluminum is in any way related to sporadic
Alzheimer’s disease in the general population (Letzel et al., 2000).
Axonopathies
The neurotoxic disorders termed axonopathies are those in which
the primary site of toxicity is the axon itself. The axon degenerates, and with it the myelin surrounding that axon; however, the
neuron cell body remains intact (Fig. 16-4). John Cavanagh coined
the term dying-back neuropathy as a synonym for axonopathy (Cavanagh, 1964). The concept of “dying back” postulated that the focus of toxicity was the neuronal cell body itself and that the distal axon degenerated progressively from the synapse, back toward
the cell body with increasing injury. It now appears that, in the
best-studied axonopathies, a different pathogenetic sequence occurs; the toxicant results in a “chemical transection” of the axon
at some point along its length, and the axon distal to the transection, biologically separated from its cell body, degenerates.
Because longer axons have more targets for toxic damage than
shorter axons, one would predict that longer axons would be more
affected in toxic axonopathies. Indeed, such is the case. The involvement of long axons of the CNS, such as ascending sensory
axons in the posterior columns or descending motor axons, along
with long sensory and motor axons of the PNS, prompted Spencer
and Schaumburg (1976) to suggest that the toxic axonopathies in
which the distal axon was most vulnerable be called central peripheral distal axonopathies, which, though cumbersome, accurately depicts the pathologic sequence.
A critical difference exists in the significance of axonal degeneration in the CNS compared with that in the PNS: peripheral
axons can regenerate whereas central axons cannot. In the PNS,
glial cells and macrophages create an environment supportive of
axonal regeneration, and Schwann cells transplanted to the CNS
maintain this ability. In the CNS, release of inhibitory factors from
damaged myelin and astrocyte scarring actually interfere with regeneration (Qui, 2000). Interestingly, when this glial interference
is removed through transplantation of CNS neurons to the PNS,
the neurons are capable of extending neurites. But there appears to
be more than just glial interference to account for the lack of CNS
regeneration. The observation that embryonic neurons can overcome glial interference when placed into the adult NS is consistent with the development of an intrinsic sensitivity to inhibitory
factors during maturation. Therefore, the inability of the CNS to
regenerate appears to be due to both unfavorable environmental
glial factors and properties of the mature neuron. The clinical relevance of the disparity between the CNS and PNS is that partial
recovery—or, in mild cases, complete recovery—can occur after
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
12:26 PM
Page 547
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
the CNS also develop neurofilament-filled swellings distally, but
axonal degeneration is seen much less often. The attribute of the
neurofilament that seemingly determines it as the toxicologically
relevant target is its slow rate of transport down the axon (Nixon
and Sihag, 1991), predisposing it to progressive derivatization and
cross-linking.
Hexane neuropathy is one of the best understood of the toxic
neuropathies, and much of this understanding has stemmed from
controversy over whether pyrrole formation alone is the injury (an
arylation reaction) or whether subsequent oxidation of pyrroles
leading to covalent protein cross-linking is a necessary step (Amarnath et al., 1994). The question was apparently resolved in experiments with a novel -diketone, 3-acetyl-2,5-hexanedione (AcHD)
(St. Clair et al., 1988). AcHD results in very rapid pyrrole formation both in vitro and in vivo. However, the electron-withdrawing
acetyl group renders the resulting pyrrole essentially inert, so that
it does not undergo oxidation. Despite massive pyrrole derivatization, AcHD results in neither clinical nor morphologic evidence of
neurotoxicity. Thus, pyrrole derivatization is not sufficient to produce the neurofilamentous swellings; pyrrole oxidation, followed
by nucleophilic attack and neurofilament cross-linking, seems to
be necessary for neurotoxicity. The extent to which the accumulation is directly responsible for impaired fast axonal transport and
axonal degeneration is unclear. Recent observations from transgenic animals lacking axonal neurofilaments suggest that HD impairs fast axonal transport even in the absence of neurofilaments
(Stone et al., 1999).
The pathologic processes of neurofilament accumulation and
degeneration of the axon are followed by the emergence of a clinical peripheral neuropathy. Experimental animals become progressively weak, beginning in the hind limbs. With continued exposure, the axonopathy may progress, leading to successive weakness
in more proximal muscle groups. This is precisely the sequence of
events in humans as well, and the initial stocking-and-glove distribution of sensory loss progresses to involve more proximal segments of sensory and motor axons.
Co
py
rig
hte
dM
ate
ria
l
axonal degeneration in the PNS, whereas the same event is irreversible in the CNS.
Axonopathies can be considered to result from a chemical
transection of the axon. The number of axonal toxicants is large
and increasing in number (Table 16-2); however, they may be
viewed as a group, all of which result in the pathologic loss of distal axons with the survival of the cell body. Because the axonopathies pathologically resemble the actual physical transection
of the axon, axonal transport appears to be a likely target in many
of the toxic axonopathies. Furthermore, as these axons degenerate,
the result is most often the clinical condition of peripheral neuropathy, in which sensations and motor strength are first impaired
in the most distal extent of the axonal processes, the feet and hands.
With time and continued injury, the deficit progresses to involve
more proximal areas of the body and the long axons of the spinal
cord. The potential for regeneration is great when the insult is limited to peripheral nerves and may be complete in axonopathies in
which the initiating event can be determined and removed.
Gamma-Diketones Since the late 1960s and early 1970s, it has
been appreciated that humans develop a progressive sensorimotor
distal axonopathy when exposed to high concentrations of a simple alkane, n-hexane, day after day in work settings (Yamamura,
1969) or after repeated intentional inhalation of hexane-containing
glues. This axonopathy can be reproduced in its entirety in rats and
larger species after weeks to months of exposure to n-hexane or its
oxidative metabolites (Krasavage et al., 1980).
The subsequent observation that methyl n-butyl ketone (2hexanone) resulted in a neuropathy identical to that caused by nhexane prompted elucidation of the metabolism of these two 6carbon compounds. The -1 oxidation of the carbon chain
(Fig. 16-9) results ultimately in the -diketone, 2,5-hexanedione
(HD). That HD is the ultimate toxic metabolite of both n-hexane
and methyl n-butyl ketone is shown by the fact that other -diketones or -diketone precursors are similarly neurotoxic, while and -diketones are not (Krasavage et al., 1980).
The elucidation of the pathogenetic mechanism of -diketone
neuropathy has come from an understanding of the biology of the
axon and the chemistry of -diketone reactivity. The -diketones
react with amino groups in all tissues to form pyrroles (Amarnath
et al., 1991a). That pyrrole formation is an actual step in the pathogenesis of this axonopathy has been established by two observations. First, 3,3-dimethyl-2,5-hexanedione, which cannot form a
pyrrole, is not neurotoxic (Sayre et al., 1986). Second, the d,ldiastereomer of 3,4-dimethyl-2,5-hexanedione (DMHD) both
forms pyrroles faster than meso-DMHD and is more neurotoxic
than meso-DMHD (Genter et al., 1987).
While all proteins are derivatized by -diketones, the cytoskeleton of the axon, and especially the neurofilament, are very
stable proteins, making it the toxicologically significant target in
-diketone intoxication. The cellular changes are identical in rats
and humans: the development of neurofilament aggregates in the
distal, subterminal axon, which, as they grow larger, form massive
swellings of the axon, often just proximal to nodes of Ranvier. The
neurofilament-filled axonal swellings result in marked distortions
of nodal anatomy, including the retraction of paranodal myelin.
Following labeling of neurofilament proteins with radioactive precursors, the neurofilament transport is impaired in the -diketone
model (Griffin et al., 1984; Pyle et al., 1994). With continued intoxication, swellings are seen more proximally and there is degeneration of the distal axon along with its myelin. Long axons in
547
Carbon Disulfide The most significant exposures of humans to
CS2 have occurred in the vulcan rubber and viscose rayon industries. Manic psychoses were observed in the former setting and
were correlated with very high levels of exposure (Seppaleinen and
Haltia, 1980). In recent decades, interest in the human health effects has been focused on the NS and the cardiovascular system,
where injury has been documented in workers exposed to much
higher levels than those that are allowed today.
What is clearly established is the capacity of CS2 to cause a
distal axonopathy that is identical pathologically to that caused by
hexane. There is growing evidence that covalent cross-linking of
neurofilaments also underlies CS2 neuropathy through a series of
reactions that parallel the sequence of events in hexane neuropathy.
While hexane requires metabolism to 2,5-hexanedione, CS2 is itself the ultimate toxicant, reacting with protein amino groups to
form dithiocarbamate adducts (Lam and DiStefano, 1986). The
dithiocarbamate adducts of lysyl amino groups undergo decomposition to isothiocyanate adducts, electrophiles that then react with
protein nucleophiles to yield covalent cross-linking (Fig. 16-9). The
reaction of the isothiocyanate adducts with cysteinyl sulfhydryls to
form N,S-dialkyldithiocarbamate ester cross-links is reversible,
while the reaction with protein amino functions forms thiourea
cross-links irreversibly. Over time, the thiourea cross-links predominate and are most likely the most biologically significant (Amar-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
NEUROTOXICANT
Clioquinol
Encephalopathy (acute), subacute myelooptic
neuropathy (subacute)
Peripheral neuropathy
Dapsone
Dichlorophenoxyacetate
Dimethylaminopropionitrile
Ethylene oxide
Glutethimide
Gold
548
Hexane
Hydralazine
3,3-Iminodipropionitrile
Isoniazid
Lithium
Methyl n-butyl ketone
Metronidazole
Misonidazole
Nitrofurantoin
Organophosphorus
compounds
Paclitaxel (taxoids)
Platinum (cisplatin)
Pyrethroids
Pyridinethione (pyrithione)
Trichloroethylene
Vincristine (vinca
alkaloids)
Peripheral neuropathy, predominantly motor
Peripheral neuropathy (delayed)
Peripheral neuropathy, urinary retention
Peripheral neuropathy
Peripheral neuropathy (predominantly sensory)
Peripheral neuopathy (may have psychiatric
problems)
Peripheral neuropathy, severe cases have spasticity
Peripheral neuropathy
No data in humans; excitatory movement disorder
(rats)
Peripheral neuropathy (sensory), ataxia (high doses)
Lethargy, tremor, ataxia (reversible)
Peripheral neuropathy
Sensory peripheral neuropathy, ataxia, seizures
Peripheral neuropathy
Peripheral neuropathy
Headache, abdominal pain (acute; anticholinesterase)
Delayed peripheral neuropathy (motor), spasticity
Peripheral neuropathy
Ototoxicity with tinnitus, sensory peripheral
neuropathy
Movement disorders (tremor, choreoathetosis)
No reported human toxicity; weakness
(experimental animals)
Cranial (most often trigeminal) neuropathy
Peripheral neuropathy, variable autonomic
symptoms
Chang LW, Dyer RS, eds: Handbook of Neurotoxicology. New York: Marcel Dekker, 1995.
Graham DI, Lantos PL, eds: Greenfield’s Neuropathology, 6th ed. New York: Arnold, 1997.
b
b, c
c
Axonal degeneration, neuronal perikaryal filamentous aggregates; vacuolar
myopathy
Axonal degeneration (both myelinated and unmyelinated axons)
Insufficient data
Axonal degeneration (both myelinated and unmyelinated axons)
Axonal degeneration
Insufficient data
Axonal degeneration, some segmental demyelination
b, c
Axonal degeneration, early neurofilamentous swelling, PNS and spinal cord
Insufficient data
Axonal swellings, degeneration of olfactory epithelial cells, vestibular hair
cells
Axonal degeneration
Insufficient data
Axonal degeneration, early neurofilamentous swelling, PNS and spinal cord
Axonal degeneration, mostly affecting myelinated fibers; lesions of
cerebellar nuclei
Axonal degeneration
Axonal degeneration
No anatomic changes (neurotransmitter effect)
Axonal degeneration (delayed after single exposure), PNS and spinal cord
Axonal degeneration; microtubule accumulation in early stages
Axonal degeneration, axonal loss in posterior columns of spinal cord
b, c
c
b
Co
py
rig
hte
dM
ate
ria
l
Psychosis (acute), peripheral neuropathy (chronic)
Tremors, incoordination (experimental animals)
Peripheral neuropathy, weakness
Axonal degeneration, axon terminal affected in earliest stages
Axonal degeneration in the peripheral nervous system (PNS) and central
nervous system (CNS)
Axonal degeneration, early stages include neurofilamentous swelling
Insufficient data (humans); axonal swelling and degeneration
Axonal degeneration, inclusions in dorsal root ganglion cells; also vacuolar
myopathy
Axonal degeneration, spinal cord, PNS, optic tracts
Axonal degeneration (variable)
Axonal degeneration, early stages with membranous arrays in axon
terminals
Insufficient data
Axonal degeneration (PNS), neurofibrillary changes (spinal cord,
intrathecal route)
c
b, c
c
b, c
b, c
b
c
c
b
c
b, c
b, c
c
b, c
b, c
b, c
c
a–c
a–d
b, c
b
a, c
c
c
b, c
Spencer PS, Schaumburg HH, eds: Experimental and Clinical Neurotoxicology, 2d ed. New York: Oxford University Press, 2000.
Abou-Donia MB, ed: Neurotoxicology. Boca Raton, FL: CRC Press, 1993.
d
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
Page 548
Carbon disulfide
Chlordecone (Kepone)
Chloroquine
REFERENCE
12:26 PM
Peripheral neuropathy (often sensory)
Peripheral neuropathy
CELLULAR BASIS OF NEUROTOXICITY
5/1/01
Acrylamide
p-Bromophenylacetyl urea
Colchicine
a
NEUROLOGIC FINDINGS
2996R_ch16_535-563
Table 16-2
Compounds Associated with Axonal Injury (Axonopathies)
2996R_ch16_535-563
5/26/01
8:39 AM
Page 549
Co
py
rig
hte
dM
ate
ria
l
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
549
Figure 16-9. Molecular mechanisms of protein cross-linking in the neurofilamentous neuropathies.
Both 2,5-hexanedione, produced from hexane via -1 oxidation function of mixed function oxidase (MFO), and
CS2 are capable of cross-linking proteins. Pyrrole formation from 2,5-hexanedione is followed by oxidation and
reaction with adjacent protein nucleophiles. Dithiocarbamate formation from CS2 is followed by formation of
the protein-bound isothiocyanate and subsequent reaction with adjacent protein nucleophiles.
nath et al., 1991b; Valentine et al., 1992, 1995; Graham et al.,
1995).
As with hexane neuropathy, it has been postulated that the stability and long transport distance of the neurofilament determine
that this protein is the toxicologically relevant target in chronic CS2
intoxication. Nonetheless, proteins throughout the organism are derivatized and cross-linked as well. Cross-linking has been identified in erythrocyte-associated proteins including spectrin and globin as well as in the putative neurotoxic target neurofilament
subunits (Valentine et al., 1993, 1997). Analysis of cross-linking
in erythrocyte proteins has verified that cross-linking occurs
through thiourea bridges that accumulate with continuing exposure
(Erve et al., 1998a,b). Neurofilament cross-linking involves all
three subunits and also demonstrates a cumulative dose response
and temporal relationship consistent with a contributing event in
the development of the axonal neurofilamentous swellings. The
correlation of protein cross-linking in erythrocyte proteins and axonal proteins together with the ability to detect covalent modifications on peripheral proteins at subneurotoxic levels and at preneurotoxic time points suggests that modifications on peripheral
proteins can be used as biomarkers of effect for CS2 exposure.
These biomarkers together with morphologic changes have been
used to establish CS2 as the ultimate neurotoxic species in the peripheral neuropathy produced by oral administration of N,N-diethyldithiocarbamate (Johnson, 1998).
The clinical effects of exposure to CS2 in the chronic setting
are very similar to those of hexane exposure, with the development
of sensory and motor symptoms occurring initially in a stocking-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
550
5/26/01
8:43 AM
Page 550
UNIT 4 TARGET ORGAN TOXICITY
and-glove distribution. In addition to this chronic axonopathy, CS2
can also lead to aberrations in mood and signs of diffuse encephalopathic disease. Some of these are transient at first and subsequently become more long-lasting, a feature that is common in
vascular insufficiency in the nervous system. This fact, in combination with the knowledge that CS2 may accelerate the process of
atherosclerosis, suggests that some of the effects of CS2 on the
CNS are vascular in origin.
Co
py
rig
hte
dM
ate
ria
l
IDPN ,’-Iminodipropionitrile (IDPN) is a bifunctional nitrile
that causes a bizarre “waltzing syndrome,” which appears to result
from degeneration of the vestibular sensory hair cells (Llorens et
al., 1993). In addition, administration of IDPN is followed by massive neurofilament-filled swellings (Griffin and Price, 1980) of the
proximal, instead of the distal, axon (Fig. 16-10). The possibility
that the nitrile groups undergo bioactivation to generate a bifunctional cross-linking reagent is suggested by the effects of deuterium
substitution on the potency and metabolism of IDPN (Denlinger et
al., 1992, 1994). The similarity of the neurofilament-filled swellings to those seen with the -diketones and carbon disulfide is a
striking feature of this model neurotoxicant, underscoring this possibility. Axonal swellings do not occur in neurofilament-deficient
quails, supporting the notion that the disorder is caused by a selective effect of IDPN on neurofilaments (Mitsuishi et al., 1993).
Understanding of the similarities between the -diketones and
IDPN was extended when the potency of the -diketones was increased through molecular modeling. DMHD (3,4-dimethyl-2,5hexanedione) is an analog of 2,5-hexanedione that accelerates the
rates of both pyrrole formation and oxidation of the pyrrole. DMHD
is 20 to 30 times more potent as a neurotoxicant and, in addition,
the neurofilament-filled swellings occur in the proximal axon
(Anthony et al., 1983a), as in IDPN intoxication. In these models
of proximal neurofilamentous axonopathies, there is a block of neurofilament transport down the axon; thus, in this situation, the accumulation of neurofilaments results from blockage of the slow
component A of axonal transport (Griffin et al., 1978, 1984). De-
Figure 16-10. Diagram of axonopathies.
While 2,5-hexanedione results in the accumulation of neurofilaments in the distal regions of the axon, 3,4-dimethyl-2,5-hexanedione results in identical accumulation within the proximal segments. These proximal neurofilamentous swellings are quite similar to those that occur in the toxicity of ,-iminodipropionitrile (IDPN),
although the distal axon does not degenerate in IDPN axonopathy but becomes atrophic. Pyridinethione results
in axonal swellings that are distended with tubulovesicular material, followed by distal axonal degeneration.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/26/01
8:43 AM
Page 551
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
compounds, which are used as pesticides and as additives in plastics and petroleum products, inhibit acetylcholinesterase and create a cholinergic excess. However, as tens of thousands of humans
could attest, tri-ortho-cresyl phosphate (TOCP) may also cause a
severe central peripheral distal axonopathy without inducing
cholinergic poisoning. An epidemic of massive proportion occurred
during Prohibition in the United States, when a popular drink (Ginger Jake) was contaminated with TOCP. Another outbreak occurred
in Morocco when olive oil was adulterated with TOCP. Human
cases of paralysis have also occurred after exposure to the herbicides and cotton defoliants EPN (O-ethyl O-4-nitrophenyl
phenylphosphonothionate) and leptophos [O-(4-bromo-2,5dichlorophenyl) O-methyl phenylphosphonothionate] (AbouDonia and Lapadula, 1990).
The hydrophobic organophosphorus compounds readily enter
the NS, where they alkylate or phosphorylate macromolecules and
lead to delayed-onset neurotoxicity. There are probably multiple
targets for attack by organophosphorus esters, but which targets are
critically related to axonal degeneration is not clear. Not all of the
organophosphorus esters that inhibit acetylcholinesterase lead to a
delayed neurotoxicity. While these “nontoxic” organophosphorus
esters inhibit most of the esterase activity of the NS, there is another esterase activity, or neuropathy target esterase (NTE), that is
inhibited by the neurotoxic organophosphorus esters. Furthermore,
there is a good correlation between the potency of a given
organophosphorus ester as an axonal toxicant and its potency as
an inhibitor of NTE, both in vivo and in culture systems (Funk et
al., 1994). Neither the normal function for this enzyme activity nor
its relation to axonal degeneration is understood (Lotti et al., 1993).
Certain neurotoxic esterase inhibitors—including phosphonates,
carbamates, thiocarbamates and sulfonyl fluorides—that do not
cause significant neurotoxicity can protect against organophosphate-induced delayed neurotoxicity when given before neurotoxic
organophosphates. It has been proposed that these compounds protect through partial inhibition of neurotoxic esterase. In contrast,
when these protective neurotoxic esterase inhibitors are administerd up to 12 days following exposure to a neurotoxic organophosphate, the delayed neurotoxicity is enhanced, such that lower initial levels of neurotoxic esterase inhibition are required to produce
a delayed neuropathy (Moretto, 2000). Although the promoting
agents inhibit neurotoxic esterase, this enzyme is not thought to be
the target of promotion. The level of neurotoxic esterase inhibition
produced by the promoter is not related to the level of promotion
observed, and these promoters appear to exacerbate axonopathies
from other etiologic agents as well, such as trauma and 2,5-hexanedione exposure.
The degeneration of axons does not commence immediately
after acute organophosphorus ester exposure but is delayed for 7
to 10 days between the acute high-dose exposure and the clinical
signs of axonopathy. The axonal lesion in the PNS appears to be
readily repaired, and the peripheral nerve becomes refractory to
degeneration after repeated doses. By contrast, axonal degeneration in the long tracks of the spinal cord is progressive, resulting
in a clinical picture that may resemble multiple sclerosis.
Co
py
rig
hte
dM
ate
ria
l
creasing the rate of intoxication with DMHD changes the location
of the swellings to more distal locations, suggesting that the neurofilamentous axonopathies have a common mechanism and that
the position of the neurofilamentous swellings along the axon reflects the rate at which this process occurs (Anthony et al., 1983b).
An important difference is seen between the two proximal
neurofilamentous axonopathies caused by IDPN and DMHD, however. After DMHD intoxication, animals become progressively paralyzed in all four limbs, corresponding with marked degeneration
of the axon distal to the swellings. By contrast, the axon distal to
IDPN-induced swellings undergoes atrophy, not degeneration, and
the animal does not experience the same muscle weakness or paralysis. This observation suggests not only that axonal degeneration
is required before muscle weakness develops but also that the presence of neurofilamentous aggregates in the proximal axon is not
incompatible with the survival of the distal axon.
551
Acrylamide Acrylamide is a vinyl monomer used in the manufacture of paper products, as a flocculant in water treatment, as a
soil-stabilizing and waterproofing agent, and for making polyacrylamide gels in the research laboratory. While cautious handling
of acrylamide in the laboratory should be encouraged, human poisonings have been largely limited to factory and construction workers exposed to high doses (Kesson et al., 1977; Myers and Macun,
1991; Collins et al., 1989).
The neuropathy induced by acrylamide is a toxic distal axonopathy, beginning with degeneration of the nerve terminal. Continued intoxication results in degeneration of the more proximal
axon, a sequence of events that recapitulates what one would expect in “dying back” process. The neuropathy appears identical
whether acrylamide is administered in a single dose or in multiple
smaller doses (Crofton et al., 1996). The earliest changes are seen
in pacinian corpuscles, then in muscle spindles and motor nerve
terminals. Within nerve terminals, early events include decreased
densities of synaptic vesicles and mitochondria and accumulations
of neurofilaments and tubulovesicular profiles (DeGrandechamp et
al., 1990), along with evidence for terminal sprouting (DeGrandechamp and Lowndes, 1990). Multifocal accumulations of
membranous bodies, mitochondria, and neurofilaments are observed in the distal axon, suggesting abnormal axonal transport.
Indeed, retrograde fast transport has been shown to be impaired by
acrylamide exposure (Padilla et al., 1993) and appears to occur before any morphologic changes are evident in axons or their terminals. Abnormalities in fast axonal transport have been observed in
peripheral nerve axons from transgenic animals lacking neurofilaments when exposed in vitro to acrylamide (Stone et al., 1999).
Studies employing chick or rat embryo neuron cultures have
demonstrated that both anterograde and retrograde fast axonal
transport are inhibited by acrylamide (Harris et al., 1994). These
effects are clearly not the result of ATP depletion. In addition, specific alterations of growth cone structure, including loss of filopodial elements, follow exposure to acrylamide, and these are separable from the effects of ATP depletion and sulfhydryl alkylation
(Martenson et al., 1995). Because the growth cone of growing neurites in culture has many similarities to the axon terminal in vivo,
it has been suggested that the growth cone alterations are a good
model for the initial reactions of acrylamide with its axon terminal target(s).
Organophosphorus Esters Many toxicologists and most physicians who practice in rural areas are aware of the acute cholinergic poisoning induced by certain organophosphorus esters. These
Pyridinethione Zinc pyridinethione has antibacterial and antifungal properties and is a component of shampoos that are effective in the treatment of seborrhea and dandruff. Because the compound is directly applied to the human scalp, it caused some
concern when it was discovered that zinc pyridinethione is neurotoxic in rodents. Rats, rabbits, and guinea pigs all develop a distal
axonopathy when zinc pyridinethione is a contaminant of their food
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
552
5/26/01
8:44 AM
Page 552
UNIT 4 TARGET ORGAN TOXICITY
tubulin migrates down the axon. Thus, the tubules are constantly
associating and dissociating. It is within this dynamic equilibrium
that paclitaxel and the vinca alkaloids exert their toxic effects, preventing the interchange of the two pools of tubulin (Fig. 16-11).
The morphology of the axon is, of course, different in the two
situations. In the case of colchicine, the axon appears to undergo
atrophy and there are fewer microtubules within the axons. In contrast, following exposure to paclitaxel, microtubules are present in
great numbers and are aggregated to create arrays of microtubules
(Roytta et al., 1984; Roytta and Raine, 1986). Both situations probably interfere with the process of fast axonal transport, although
this has not yet been demonstrated definitively with paclitaxel. In
both situations, the resultant clinical condition is a peripheral
neuropathy.
Co
py
rig
hte
dM
ate
ria
l
(Sahenk and Mendell, 2000). Fortunately, however, zinc pyridinethione does not penetrate skin well, and it has not resulted in
human injury to date.
Although the zinc ion is an important element of the therapeutic action of the compound, only the pyridinethione moiety is
absorbed following ingestion, with the majority of zinc eliminated
in the feces. In addition, sodium pyridinethione is also neurotoxic,
establishing that it is the pyridinethione that is responsible for the
neurotoxicity. Pyridinethione chelates metal ions and, once oxidized to the disulfide, may lead to the formation of mixed disulfides with proteins. However, which of these properties, if either,
is the molecular mechanism of its neurotoxicity remains unknown.
Although these molecular issues remain to be resolved,
pyridinethione appears to interfere with the fast axonal transport
systems. While the fast anterograde system is less affected,
pyridinethione impairs the turnaround of rapidly transported vesicles and slows the retrograde transport of vesicles (Sahenk and
Mendell, 1980). This aberration of the fast axonal transport systems is the most likely physiologic basis of the accumulation of
tubular and vesicular structures in the distal axon (Fig. 16-10). As
these materials accumulate in one region of the axon, they distend
the axonal diameter, resulting in axonal swellings filled with
tubulovesicular profiles. As in many other distal axonopathies, the
axon degenerates in its more distal regions beyond the accumulated structures. The earliest signs are diminished grip strength and
electrophysiologic changes of the axon terminal, with normal conduction along the proximal axon in the early stages of exposure
(Ross and Lawborn, 1990). Ultimately, the functional consequence
of the axonal degeneration in this exposure is similar to that of
other axonopathies—namely, a peripheral neuropathy.
Microtubule-Associated Neurotoxicity The role of microtubules
in axonal transport and in the maintenance of axonal viability is
still being elucidated; however, the biochemistry and toxicity of
several alkaloids isolated from plants have greatly aided the understanding of these processes. The first of these historically are
the vinca alkaloids and colchicine, which bind to tubulin and inhibit the association of this protein subunit to form microtubules.
Vincristine, one of the vinca alkaloids, has found clinical use in
the treatment of leukemia due to the antimitotic activity of its microtubule-directed action. Colchicine, in contrast, is used primarily
in the treatment of gout. Both of these microtubule inhibitors also
have been the cause of peripheral neuropathies in patients (Verity,
1997).
Much more recently another plant alkaloid, paclitaxel (Taxol)
has been described that has a significantly different interaction with
microtubules. Paclitaxel binds to tubules when they are assembled
and stabilizes the polymerized form of tubules, so that they remain
assembled even in the cold or in the presence of calcium, conditions under which microtubules normally dissociate into tubulin
subunits (Schiff and Horwitz, 1981). Paclitaxel has also found its
way into clinical usage as a treatment of certain cancers and has
resulted in sensorimotor axonopathy—in patients receiving large
doses of this compound (Lipton et al., 1989; Sahenk et al., 1994)
—or in autonomic neuropathy (Jerian et al., 1993).
It is fascinating that both the depolymerization of tubules by
colchicine and the vinca alkaloids and the stabilization of tubules
by paclitaxel lead to an axonopathy. It has been known for some
time that microtubules are in a state of dynamic equilibrium in
vitro, with tubules existing in equilibrium with dissociated subunits. This process almost certainly occurs in vivo as well, even as
Myelinopathies
Myelin provides electrical insulation of neuronal processes, and its
absence leads to a slowing of conduction and aberrant conduction
of impulses between adjacent processes, so-called ephaptic transmission. Toxicants exist that result in the separation of the myelin
lamellae, termed intramyelinic edema, and in the selective loss of
myelin, termed demyelination (Fig. 16-4). Intramyelinic edema
may be caused by alterations in the transcript levels of myelin basic protein-mRNA (Veronesi et al., 1991) and early in its evolution
is reversible. However, the initial stages may progress to demyelination, with loss of myelin from the axon. Demyelination may also
result from direct toxicity to the myelinating cell. Remyelination
in the CNS occurs to only a limited extent after demyelination.
However, Schwann cells in the PNS are capable of remyelinating
the axon after a demyelinating injury. Interestingly, remyelination
after segmental demyelination in peripheral nerve involves multiple Schwann cells and results, therefore, in internodal lengths (the
distances between adjacent nodes of Ranvier) that are much shorter
than normal and a permanent record of the demyelinating event.
The compounds in Table 16-3 all lead to a myelinopathy.
Some of these compounds have created problems in humans, and
Figure 16-11. Neurotoxicants directed toward microtubules.
Colchicine leads to the depolymerization of microtubules by binding to the
tubulin monomers and preventing their association into tubules. Paclitaxel
stabilizes the microtubules, preventing their dissociation into subunits under conditions in which they would normally dissociate. Both compounds
interfere with the normal dynamic equilibrium that exists between tubulin
monomers and microtubules, and both are neurotoxic.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
5/1/01
12:26 PM
NEUROTOXICANT
CELLULAR BASIS OF NEUROTOXICITY
553
Not reported in humans; hyperexcitability, tremors (rats)
Intramyelinic edema; pigment accumulation in neurons
b, c
Peripheral neuropathy
b, c
Cuprizone
Not reported in humans; encephalopathy (experimental animals)
Disulfiram
Ethidium bromide
Hexachlorophene
Peripheral neuropathy, predominantly sensory
Insufficient data (humans)
Irritability, confusion, seizures
Lysolecithin
Effects only on direct injection into peripheral nervous system
(PNS) or central nervous system (CNS) (experimental
animals)
Peripheral neuropathy
Hydrocephalus, hind-limb paralysis (experimental animals)
Headache, photophobia, vomiting, paraplegia (irreversible)
Axonal degeneration and demyelination; lipid-laden lysosomes in
Schwann cells
Status spongiosis of white matter, intramyelinic edema (early stages);
gliosis (late)
Axonal degeneration, swellings in distal axons
Intramyelinic edema, status spongiosis of white matter
Brain swelling, intramyelinic edema in CNS and PNS, late axonal
degeneration
Selective demyelination
Demyelinating neuropathy, membrane-bound inclusions in Schwann cells
Demyelinating neuropathy, lipofuscinosis (experimental animals)
Brain swelling (acute) with intramyelinic edema, spongiosis of white
matter
b, c
b
a–c
Chang LW, Dyer RS, eds: Handbook of Neurotoxicology. New York: Marcel Dekker, 1995.
Graham DI, Lantos PL, eds: Greenfield’s Neuropathology, 6th ed. New York: Arnold, 1997.
c
Spencer PS, Schaumburg HH, eds: Experimental and Clinical Neurotoxicology, 2d ed. New York: Oxford University Press, 2000.
b
REFERENCE
Acetylethyltetramethyl
tetralin (AETT)
Amiodarone
Perhexilene
Tellurium
Triethyltin
a
NEUROLOGIC FINDINGS
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
b, c
b
c
b, c
b
Page 553
Co
py
rig
hte
dM
ate
ria
l
2996R_ch16_535-563
Table 16-3
Compounds Associated with Injury of Myelin (Myelinopathies)
2996R_ch16_535-563
554
5/2/01
6:42 AM
Page 554
UNIT 4 TARGET ORGAN TOXICITY
hibited by tellurium (Wagner et al., 1995), and its inhibition also
occurs with certain organotellurium compounds, with a correlation
between the potency of enzyme inhibition and demyelination in
vivo (Goodrum, 1998).
At the same time as these biochemical changes are occurring,
lipids accumulate in Schwann cells within intracytoplasmic vacuoles; shortly afterwards, these Schwann cells lose their ability to
maintain myelin. Axons and the myelin of the CNS are impervious to the effects of tellurium. However, individual Schwann cells
in the PNS disassemble their concentric layers of myelin membranes, depriving the adjacent intact axon of its electrically insulated status. Not all Schwann cells are equally affected by the
process; rather, those Schwann cells that encompass the greatest
distances appear to be the most affected. These cells are associated
with the largest-diameter axons, encompass the longest intervals
of myelination, and provide the thickest layers of myelin. Thus, it
appears that the most vulnerable cells are those with the largest
volume of myelin to support (Bouldin et al., 1988).
As the process of remyelination begins, several cells cooperate to reproduce the myelin layers that were previously formed by
a single Schwann cell. Perhaps this diminished demand placed
upon an individual cell is the reason that remyelination occurs even
in the presence of continued exposure to tellurium (Bouldin et al.,
1988). The expression of the neurologic impairment is also short
in duration, reflecting the transient cellular and biochemical events.
The animals initially develop severe weakness in the hind limbs
but then recover their strength after 2 weeks on the tellurium-laden
diet.
Co
py
rig
hte
dM
ate
ria
l
many have been used as tools to explore the process of myelination of the NS and the process of remyelination following toxic
disruption of myelin. In general, the functional consequences of
demyelination depend on the extent of the demyelination and
whether it is localized within the CNS or the PNS or is more diffuse in its distribution. Those toxic myelinopathies in which the
disruption of myelin is diffuse generate a global neurologic deficit,
whereas those that are limited to the PNS produce the symptoms
of peripheral neuropathy.
Hexachlorophene Hexachlorophene, or methylene 2,2-methylenebis(3,4,6-trichlorophenol), resulted in human neurotoxicity
when newborn infants, particularly premature infants, were bathed
with the compound to avoid staphylococcal skin infections (Mullick, 1973). Following skin absorption of this hydrophobic compound, hexachlorophene enters the NS and results in intramyelinic
edema, splitting the intraperiod line of myelin in both the CNS and
the PNS. The intramyelinic edema leads to the formation of vacuoles, creating a “spongiosis” of the brain (Purves et al., 1991).
Experimental studies with erythrocyte membranes show that hexachlorophene binds tightly to cell membranes, resulting in the loss
of ion gradients across the membrane (Flores and Buhler, 1974).
It may be that hexachlorophene results in loss of the ability to exclude ions from between the layers of myelin and that, with ion
entry, water also separates the myelin layers as “edema.” Another,
perhaps related effect is the uncoupling of mitochondrial oxidative
phosphorylation by hexachlorophene (Cammer and Moore, 1974),
because this process is dependent on a proton gradient. Intramyelinic edema is reversible in the early stages, but with increasing exposure, hexachlorophene causes segmental demyelination. Swelling of the brain causes increased intracranial pressure,
which may be fatal in and of itself. With high-dose exposure, axonal degeneration is seen, along with degeneration of photoreceptors in the retina. It has been postulated that the pressure from severe intramyelinic edema may also injure the axon, leading to
axonal degeneration, and endoneurial pressure measurements support this idea (Myers et al., 1982). The toxicity of hexachlorophene
expresses itself functionally in diffuse terms that reflect the diffuse
process of myelin injury. Humans exposed acutely to hexachlorophene may have generalized weakness, confusion, and
seizures. Progression may occur, to include coma and death.
Tellurium Although human cases have not been reported, neurotoxicity of tellurium has been demonstrated in animals. Young
rats exposed to tellurium in their diet develop a severe peripheral
neuropathy. Within the first 2 days of beginning a diet containing
tellurium, the synthesis of myelin lipids in Schwann cells displays
some striking changes (Harry et al., 1989). There is a decreased
synthesis of cholesterol and cerebrosides, lipids richly represented
in myelin, whereas the synthesis of phosphatidylcholine, a more
ubiquitous membrane lipid, is unaffected. Myelin protein mRNA
steady-state levels are down-regulated (Morell et al., 1994). The
synthesis of free fatty acids and cholesterol esters increases to some
degree, and there is a marked elevation of squalene, a precursor of
cholesterol. These biochemical findings demonstrate that there are
a variety of lipid abnormalities, and the simultaneous increase in
squalene and decrease in cholesterol suggest that tellurium or one
of its derivatives may interfere with the normal conversion of squalene to cholesterol. Squalene epoxidase, a microsomal monooxygenase that utilizes NAPDH cytochrome P450 reductase, has been
strongly implicated as the target of tellurium. It is specifically in-
Lead Lead exposure in animals results in a peripheral neuropathy with prominent segmental demyelination, a process that bears
a strong resemblance to tellurium toxicity (Dyck et al., 1977). However, the neurotoxicity of lead is much more variable in humans
than in rats, and there are also a variety of manifestations of lead
toxicity in other organ systems.
The neurotoxicity of lead has been appreciated for centuries.
In current times, adults are exposed to lead in occupational settings
through lead smelting processes and soldering and in domestic settings through lead pipes or through the consumption of “moonshine” contaminated with lead. In addition, some areas contain
higher levels of environmental lead, resulting in higher blood levels in the inhabitants. Children, especially those below 5 years of
age, have higher blood levels of lead than adults in the same environment, due to the mouthing of objects and the consumption of
substances other than food. The most common acute exposure in
children, however, has been through the consumption of paint chips
containing lead pigments (Perlstein and Attala, 1966), a finding
that has led to public efforts to prevent the use of lead paints in
homes with children.
In young children, acute massive exposures to lead result in
severe cerebral edema, perhaps from damage to endothelial cells.
Children seem to be more susceptible to this lead encephalopathy
than adults (Johnston and Goldstein, 1998); however, adults may
also develop an acute encephalopathy in the setting of massive lead
exposure.
Chronic lead intoxication in adults results in peripheral neuropathy, often accompanied by manifestations outside the NS, such
as gastritis, colicky abdominal pain, anemia, and the prominent
deposition of lead in particular anatomic sites, creating lead lines
in the gums and in the epiphyses of long bones in children. The
effects of lead in the peripheral nerve of humans (lead neuropathy)
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
12:26 PM
Page 555
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
drug in the blood. The structural similarity of many compounds
with similar actions has led to the recognition of specific categories
of drugs and toxins. For example, some mimic the process of neurotransmission of the sympathetic nervous system and are termed
the sympathomimetic compounds. As the targets of these drugs are
located throughout the body, the responses are not localized; however, the responses are stereotyped in that each member of a class
tends to have similar biological effects. In terms of toxicity, most
of the side effects of these drugs may be viewed as short-term interactions that are easily reversible with time or that may be counteracted by the use of appropriate antagonists. However, some of
the toxicity associated with long-term use is irreversible. For example, phenothiazines, which have been used to treat chronic schizophrenia for long periods of time, may lead to the condition of tardive dyskinesia, in which the patient is left with a permanent
disability of prominent facial grimaces (DeVeaugh-Geiss, 1982).
Both reversible acute high-dose toxicity and sustained effects
following chronic exposure are common features of the agents that
interact with the process of neurotransmission. Some compounds
which have neurotransmitter-associated toxicity are listed in
Table 16-4.
Co
py
rig
hte
dM
ate
ria
l
is not entirely understood. Electrophysiologic studies have demonstrated a slowing of nerve conduction. While this observation is
consistent with the segmental demyelination that develops in experimental animals, pathologic studies in humans with lead neuropathy typically have demonstrated an axonopathy. Another finding in humans is the predominant involvement of motor axons,
creating one of the few clinical situations in which patients present with predominantly motor symptoms. The basis for the effect
on the brain (lead encephalopathy) is also unclear, although an effect on the membrane structure of myelin and myelin membrane
fluidity has been shown (Dabrowski-Bouta et al., 1999).
Although the manifestations of acute and chronic exposures
to lead have been long established, it is only in recent years that
the concept has emerged that extremely low levels of exposure to
lead in “asymptomatic” children may have an effect on their intelligence. Initial reports noted a relationship between mild elevations of blood lead in children and school performance; more
recently, correlations between elevated lead levels in decidual teeth
and performance on tests of verbal abilities, attention, and behavior (nonadaptive) have been demonstrated (Needleman and
Gatsonis, 1990; Needleman, 1994). Although there is a clear association between lead level and intellectual performance, there has
been some discussion as to whether lead is causal. Children with
higher blood levels tend to share certain other environmental factors, such as socioeconomic status and parental educational level.
However, in spite of these complex social factors, it appears that
lead exposure has an adverse effect on the intellectual abilities of
children (Needleman, 1994), an association between lead exposure
and brain dysfunction that has received experimental support in animal models (Gilbert and Rice, 1987) and has prompted screening
for lead in children (Benjamin and Platt, 1999).
Neurotransmission-Associated
Neurotoxicity
Many neurotoxicants destroy cellular structures within the NS, providing anatomic footprints of their toxicity. In some instances, however, dysfunction of the NS may occur without evidence of altered
cellular structures; rather, the neurotoxicity expresses itself in terms
of altered behavior or impaired performance on neurologic tests.
In fact, many of the neurotoxic agents that lead to anatomic evidence of cellular injury were first demonstrated to be neurotoxic
through the detection of neurologic dysfunction.
Molecular mechanisms are not understood for some of these
agents; however, there is a group of such compounds in which the
chemical basis of their action is clear. These are the toxicants that
impair the process of neurotransmission. A wide variety of naturally occurring toxins as well as synthetic drugs interact with specific mechanisms of intercellular communication. At times, interruption of neurotransmission is beneficial to an individual, and the
process may be viewed as neuropharmacology. However, excessive or inappropriate exposure to compounds that alter neurotransmission may be viewed as one of the patterns of neurotoxicology.
This group of compounds may interrupt the transmission of
impulses, block or accentuate transsynaptic communication, block
reuptake of neurotransmitters, or interfere with second-messenger
systems. In general, the acute effects of these compounds are directly related to the immediate concentration of the compound at
the active site, which bears a direct relationship to the level of the
555
Nicotine Widely available in tobacco products and in certain pesticides, nicotine has diverse pharmacologic actions and may be the
source of considerable toxicity. These toxic effects range from
acute poisoning to more chronic effects. Nicotine exerts its effects
by binding to a subset of cholinergic receptors, the nicotinic receptors. These receptors are located in ganglia, at the neuromuscular junction, and also within the CNS, where the psychoactive
and addictive properties most likely reside. Smoking and “pharmacologic” doses of nicotine accelerate heart rate, elevate blood
pressure, and constrict blood vessels within the skin. Because the
majority of these effects may be prevented by the administration
of - and -adrenergic blockade, these consequences may be
viewed as the result of stimulation of the ganglionic sympathetic
nervous system (Benowitz, 1986). At the same time, nicotine leads
to a sensation of “relaxation” and is associated with alterations of
electroencephalographic (EEG) recordings in humans. These
effects are probably related to the binding of nicotine with nicotinic receptors within the CNS, and the EEG changes may be
blocked with mecamylamine, an antagonist.
Acute overdose of nicotine has occurred in children who accidentally ingest tobacco products, in tobacco workers exposed to
wet tobacco leaves (Gehlbach et al., 1974), and in workers exposed
to nicotine-containing pesticides. In each of these settings, the rapid
rise in circulating levels of nicotine leads to excessive stimulation
of nicotinic receptors, a process that is followed rapidly by ganglionic paralysis. Initial nausea, rapid heart rate, and perspiration
are followed shortly by marked slowing of heart rate with a fall in
blood pressure. Somnolence and confusion may occur, followed
by coma; if death results, it is often the result of paralysis of the
muscles of respiration.
Such acute poisoning with nicotine fortunately is uncommon.
Exposure to lower levels for longer duration, in contrast, is very
common, and the health effects of this exposure are of considerable epidemiologic concern. In humans, however, it has been impossible so far to separate the effects of nicotine from those of
other components of cigarette smoke. The complications of smoking include cardiovascular disease, cancers (especially malignancies of the lung and upper airway), chronic pulmonary disease, and
attention deficit disorders in children of women who smoke dur-
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
5/1/01
12:26 PM
NEUROTOXICANT
556
a
NEUROLOGIC FINDINGS
Amphetamine and
methamphetamine
Tremor, restlessness (acute); cerebral infarction and
hemorrhage; neuropsychiatric disturbances
Atropine
Cocaine
Restlessness, irritability, hallucinations
Increased risk of stroke and cerebral atrophy (chronic users);
increased risk of sudden cardiac death; movement and
psychiatric abnormalities, especially during withdrawal
Decreased head circumference (fetal exposure)
Domoic acid
Headache, memory loss, hemiparesis, disorientation, seizures
Kainate
Insufficient data in humans; seizures in animals (selective
lesioning compound in neuroscience)
-N-Methylamino-Lalanine (BMAA)
Muscarine (mushrooms)
Nicotine
Weakness, movement disorder (monkeys)
-N-Oxalylamino-Lalanine (BOAA)
Seizures
Nausea, vomiting, headache
Nausea, vomiting, convulsions
CELLULAR BASIS OF NEUROTOXICITY
Bilateral infarcts of globus pallidus, abnormalities in dopaminergic,
serotonergic, cholinergic systems
Acts at adrenergic receptors
Block cholinergic receptors (anticholinergic)
Infarcts and hemorrhages; alteration in striatal dopamine
neurotransmission (binds to voltage-gated sodium channels)
b, c
b, c
b, c
Structural malformations in newborns
Neuronal loss, hippocampus and amygdala, layers 5 and 6 of neocortex
Kainate-like pattern of excitotoxicity
Degeneration of neurons in hippocampus, olfactory cortex, amygdala,
thalamus
Binds AMPA/kainate receptors
Degenerative changes in motor neurons (monkeys)
Excitotoxic probably via NMDA receptors
Binds muscarinic receptors (cholinergic)
Binds nicotinic receptors (cholinergic) low-dose stimulation; high-dose
blocking
Excitotoxic probably via AMPA class of glutamate receptors
Graham DI, Lantos PL, eds: Greenfield’s Neuropathology, 6th ed: New York: Arnold, 1997.
Spencer PS, Schaumburg HH, eds: Experimental and Clinical Neurotoxicology, 2d ed. New York: Oxford University Press, 2000.
c
Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds: Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 9th ed. New York: McGraw-Hill, 1996.
b
REFERENCE
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
a, b
a
a, b
c
b, c
a, b
Page 556
Co
py
rig
hte
dM
ate
ria
l
2996R_ch16_535-563
Table 16-4
Compounds Associated with Neurotransmitter-Associated Toxicity
2996R_ch16_535-563
5/26/01
8:45 AM
Page 557
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
Kaku and Lowenstein, 1990). While the mechanisms for these effects are not known, imaging studies have demonstrated increased
cerebrovascular resistance in cocaine abusers (Herning et al.,
1999). Chronic cocaine abuse has been associated with neurodegenerative changes in the striatum, and these changes are thought
to underlie some of the neurologic and psychiatric outcomes in
chronic cocaine abusers (Wilson et al., 1996b).
Like cocaine, amphetamines exert their effects in the CNS by
altering catecholamine neurotransmission; however, unlike cocaine, the actions of amphetamines are not limited to plasma membrane transporters but also appear to involve disruption of vesicular storage of dopamine. Analogous to cocaine, amphetamines have
been associated with an increased risk of abnormal fetal growth
and development, increased risk of cerebrovascular disease, and increased risk of psychiatric and neurologic problems in chronic
abusers that may be related to dopaminergic neurodegeneration
(Wilson et al., 1996a).
Co
py
rig
hte
dM
ate
ria
l
ing pregnancy. Nicotine may be a factor in some of these problems. For example, an increased propensity for platelets to aggregate is seen in smokers, and this platelet abnormality correlates
with the level of nicotine. Nicotine also places an increased burden on the heart through its acceleration of heart rate and blood
pressure, suggesting that nicotine may play a role in the onset of
myocardial ischemia (Benowitz, 1986). In addition, nicotine also
inhibits apoptosis and may play a direct role in tumor promotion
and tobacco-related cancers (Wright et al., 1993).
It seems more clear that chronic exposure to nicotine has effects on the developing fetus. Along with decreased birth weights,
attention deficit disorders are more common in children whose
mothers smoke cigarettes during pregnancy, and nicotine has been
shown to lead to analogous neurobehavioral abnormalities in animals exposed prenatally to nicotine (Lichensteiger et al., 1988).
Nicotinic receptors are expressed early in the development of the
NS, beginning in the developing brainstem and later expressed in
the diencephalon. The role of these nicotinic receptors during development is unclear; however, it appears that prenatal exposure to
nicotine alters the development of nicotinic receptors in the CNS
(van de Kamp and Collins, 1994)—changes that may be related to
subsequent attention and cognitive disorders in animals and
children.
557
Cocaine and Amphetamines Cocaine differs from nicotine in
the eyes of the law, a feature of the compound that affects the willingness of users to discuss their patterns of use. Nonetheless, it has
been possible to obtain estimates of the number of users. In 1972,
approximately 9 million college-age adults were using the drug; in
1982, it was approximately 33 million (Fishburne et al., 1983). In
urban settings, from 10 to 45 percent of pregnant women take
cocaine (Volpe, 1992), and cocaine metabolites can be detected in
as many as 6 percent of babies born at suburban hospitals
(Schutzman et al., 1991).
The euphoric and addictive properties of cocaine derive from
alterations in catecholaminergic neurotransmission, especially
enhanced dopaminergic neurotransmission, by blocking the
dopamine reuptake transporter (DAT) (Giros et al., 1996). Acute
toxicity due to excessive intake, or overdose, may result in unanticipated deaths. While the tragic accounts of celebrities’ overdoses
may attract media attention, it is the chronic “recreational” consumption of cocaine that is of greatest epidemiologic concern.
Although cocaine increases maternal blood pressure during
acute exposure in pregnant animals, the blood flow to the uterus
actually diminishes. Depending on the level of the drug in the
mother, the fetus may develop marked hypoxia as a result of the
diminished uterine blood flow (Woods et al., 1987). In a study of
women who used cocaine during pregnancy, there were more miscarriages and placental hemorrhages (abruptions) than in drug-free
women (Chasnoff et al., 1985). Impaired placental function may
be the cause for the increase in infarctions and hemorrhages in the
newborn infant who has been exposed to cocaine (Volpe, 1992). In
addition, the newborn infants of cocaine users were less interactive than normal newborns and exhibited a poor response to stimuli in the environment (Chasnoff et al., 1985). Evidence for other
forms of structural damage to brain in newborns exposed to cocaine is mixed (Behnke et al., 1998).
In addition to deleterious effects on fetal growth and development, cocaine abuse is associated with an increased risk of cerebrovascular disease, cerebral perfusion defects, and cerebral atrophy in adults (Filley and Kelly, 1993; Freilich and Byrne, 1992;
Excitatory Amino Acids Glutamate and certain other acidic
amino acids are excitatory neurotransmitters within the CNS. The
discovery that these excitatory amino acids can be neurotoxic at
concentrations that can be achieved in the brain has generated a
great amount of interest in these “excitotoxins.” In vitro systems
have established that the toxicity of glutamate can be blocked by
certain glutamate antagonists (Rothman and Olney, 1986), and the
concept has emerged that the toxicity of excitatory amino acids
may be related to such divergent conditions as hypoxia, epilepsy,
and neurodegenerative diseases (Meldrum, 1987; Choi, 1988;
Lipton and Rosenberg, 1994; Beal, 1992, 1995, 1998).
Glutamate is the main excitatory neurotransmitter of the brain
and its effects are mediated by several subtypes of receptors (Fig.
16-12) called excitatory amino acid receptors (EAARs) (Schoepfer
Figure 16-12. Schematic diagram of a synapse.
Synaptic vesicles are tranported to the axonal terminus, and released across
the synaptic cleft to bind to the postsynaptic receptors. Glutamate, as an
excitatory neurotransmitter, binds to its receptor and opens a calcium channel, leading to the excitation of the postsynaptic cell.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
558
5/1/01
12:26 PM
Page 558
UNIT 4 TARGET ORGAN TOXICITY
rodegeneration that was most prominent in the hippocampus
and amygdala but also affected regions of the thalamus and cerebral cortex.
Other foci of unusual neurodegenerative diseases also have
been evaluated for being caused by dietary exposure to EAARs.
Perhaps the best known of these is the complex neurodegenerative
disease in the indigenous population of Guam and surrounding islands that shares features of amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. Early investigations of this
Guamanian neurodegenerative complex suggested that the disorder
may be related to an environmental factor, perhaps consumption
of seeds of Cycas circinalis (Kurland, 1963). Subsequently,
-amino-methylaminopropionic acid (or B-N-methylamino-Lalanine, BMAA) was isolated from the cycad and was shown to
be neurotoxic in model systems. The toxicity of BMAA is similar
to that of glutamate in vitro and can be blocked by certain EAAR
antagonists (Nunn et al., 1987). Studies in vivo, however, have not
demonstrated a relationship between BMAA and the Guamanian
neurodegenerative complex (Spencer et al., 1987; Hugon et al.,
1988; Seawright et al., 1990; Duncan, 1992). Therefore, it remains
unresolved what role cycad consumption and environmental factors play in this cluster of atypical neurodegenerative disease.
The expanding field of the excitotoxic amino acids embodies
many of the same attributes that characterize the entire discipline
of neurotoxicology. Neurotoxicology is generally viewed as the
study of compounds that are deleterious to the NS, and the effects
of glutamate and kainate may be viewed as examples of this type
of deleterious toxicity. Exposure to these excitotoxic amino acids
leads to neuronal injury and—when of sufficient degree—may kill
neurons. However, the implications of these findings, as with the
entire field of neurotoxicology, extend beyond the direct toxicity
of the compounds in exposed populations. With kainate, as with
many other neurotoxic compounds, has come a tool for neurobiologists who seek to explore the anatomy and function of the NS.
Kainate, through its selective action on neuronal cell bodies, has
provided a greater understanding of the functions of cells within a
specific region of the brain, while previous lesioning techniques
addressed only regional functions. Finally, the questions surrounding domoic acid poisoning and the Guamanian neurodegenerative complex serve to remind the student of neurotoxicology that
the causes of many neurologic diseases remain unknown. This void
in understanding and the epidemiologic evidence that some neurodegenerative diseases may have environmental contributors provide a heightened desire to appreciate more fully the effects of elements of our environment on the NS.
Co
py
rig
hte
dM
ate
ria
l
et al., 1994; Hollmann and Heinemann, 1994; Lipton and Rosenberg, 1994). The two major subtypes of glutamate receptors are
those that are ligand-gated directly to ion channels (ionotropic) and
those that are coupled with G proteins (metabotropic). Ionotropic
receptors may be further subdivided by their specificity for binding kainate, quisqualate, and -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and N-methyl-D-aspartate
(NMDA). The entry of glutamate into the CNS is regulated at the
blood-brain barrier and, following an injection of a large dose of
glutamate in infant rodents, glutamate exerts its effects in the area
of the brain in which the blood-brain barrier is least developed, the
circumventricular organ. Within this site of limited access, glutamate injures neurons, apparently by opening glutamate-dependent
ion channels, ultimately leading to neuronal swelling and neuronal
cell death (Olney, 1978; Coyle, 1987). The toxicity affects the dendrites and neuronal cell bodies but seems to spare axons. The only
known related human condition is the “Chinese restaurant syndrome,” in which consumption of large amounts of monosodium
glutamate as a seasoning may lead to a burning sensation in the
face, neck and chest.
The cyclic glutamate analog kainate was initially isolated from
a seaweed in Japan as the active component of an herbal treatment
of ascariasis. Kainate is extremely potent as an excitotoxin, being
a hundredfold more toxic than glutamate and is selective at a molecular level for the kainate receptor (Coyle, 1987). Like glutamate,
kainate selectively injures dendrites and neurons and shows no substantial effect on glia or axons. As a result, this compound has
found use in neurobiology as a tool. Injected into a region of the
brain, kainate can destroy the neurons of that area without disrupting all of the fibers that pass through the same region. Neurobiologists, with the help of this neurotoxic tool, are able to study
the role of neurons in a particular area independent of the axonal
injuries that occur when similar lesioning experiments are performed by mechanical cutting.
Development of permanent neurologic deficits in individuals
accidentally exposed to high doses of an EAAR agonist has underscored the potential importance of EAAs in disease (Perl et al.,
1990; Teitelbaum et al., 1990). A total of 107 individuals in the
Maritime Provinces of Canada were exposed to domoic acid, an
analog of glutamate, and suffered an acute illness that most commonly presented as gastrointestinal disturbance, severe headache,
and short-term memory loss. A subset of the more severely afflicted patients was subsequently shown to have chronic memory
deficits and motor neuropathy. Neuropathologic investigation of
patients who died within 4 months of intoxication showed neu-
REFERENCES
Abou-Donia MB, Lapadula DM: Mechanisms of organophosphorus esterinduced delayed neurotoxicity: Type I and type II. Annu Rev Pharmacol Toxicol 30:405–440, 1990.
Agundez JA, Jimenex JF, Luengo A, et al: Association between the oxidative polymorphism and early onset of Parkinson’s disease. Clin Pharmacol Ther 57:291–298, 1995.
Amarnath V, Anthony DC, Amarnath K, et al: Intermediates in the PaalKnorr synthesis of pyrroles. J Org Chem 56:6924–6931, 1991a.
Amarnath V, Anthony DC, Valentine WM, et al: The molecular mechanism
of the carbon disulfide mediated crosslinking of proteins. Chem Res
Toxicol 4:148–150, 1991b.
Amarnath V, Valentine WM, Amarnath K, et al: The mechanism of nucleophilic substitution of alkylpyrroles in the presence of oxygen. Chem
Res Toxicol 7:56–61, 1994.
Anthony DC, Boekelheide K, Anderson CW, et al: The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione: II. Dimethyl substitution accelerates pyrrole formation and protein
crosslinking. Toxicol Appl Pharmacol 71:372–382, 1983a.
Anthony DC, Boekelheide K, Graham DG: The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione: I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings.
Toxicol Appl Pharmacol 71:362–371, 1983b.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
12:26 PM
Page 559
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
Cohen G, Heikkila RE: In vivo scavenging of superoxide radicals by catecholamines, in Michelson AM, McCord JM, Fridovich I (eds): Superoxide and Superoxide Dismutases. London: Academic Press, 1977,
pp 351–365.
Collins JJ, Swaen GMH, Marsh GM, et al: Mortality patterns among workers exposed to acrylamide. J Occup Med 31:614–617, 1989.
Coyle JT: Kainic acid: Insights into excitatory mechanisms causing selective neuronal degeneration, in Bock G, O’Connor M (eds): Selective
Neuronal Death. New York: Wiley, 1987, pp 186–203.
Crofton KM, Padilla S, Tilson HA, et al: The impact of dose rate on the
neurotoxicity of acrylamide: The interaction of administered dose, target tissue concentrations, tissue damage, and functional effects. Toxicol Appl Pharmacol 139:163–176, 1996.
Dabrowska-Bouta G, Sulkowski G, Bartosz G, et al: Chronic lead intoxication affects the myelin membrane status in the central nervous system of adult rats. J Mol Neurosci 13:127–139, 1999.
DeGrandchamp RL, Lowndes HE: Early degeneration and sprouting at the
rat neuromuscular junction following acrylamide administration. Neuropathol Appl Neurobiol 16:239–254, 1990.
DeGrandchamp RL, Reuhl KR, Lowndes HE: Synaptic terminal degeneration and remodeling at the rat neuromuscular junction resulting from
a single exposure to acrylamide. Toxicol Appl Pharmacol 105:422–
433, 1990.
Dejneka NS, Polavarapu R, Deng X, et al: Chromosomal localization and
characterization of the stannin (Snn) gene. Mamm Genome 9:556 –
564, 1998.
Denlinger RH, Anthony DC, Amarnath K, et al: Metabolism of 3,3-iminodipropionitrile and deuterium-substituted analogs: Potential mechanisms of detoxification and activation. Toxicol Appl Pharmacol 124:
59–66, 1994.
Denlinger RH, Anthony DC, Amarnath V, et al: Comparison of location,
severity, and dose response of proximal axonal lesions induced by
3,3-iminodipropionitrile and deuterium substituted analogs. J Neuropathol Exp Neurol 51:569–576, 1992.
DeVeaugh-Geiss J: Tardive dyskinesia: Phenomenology, pathophysiology,
and pharmacology, in Tardive Dyskinesia and Related Involuntary
Movement Disorders. Boston: John Wright PSG, 1982, pp 1–18.
Di Monte DA, Langston JW: MPTP and analogs, in Spencer PS, Schaumburg HH (eds): Experimental and Clinical Neurotoxicology. New York:
Oxford University Press, 2000, pp 812–818.
Duncan MW: -Methylamino-L-alanine (BMAA) and amyotrophic lateral
sclerosis-parkinsonism dementia of the western Pacific. Ann NY Acad
Sci 648:161–168, 1992.
Dyck PJ, O’Brien PC, Ohnishi A: Lead neuropathy: 2. Random distribution of segmental demyelination among “old internodes” of myelinated fibers. J Neuropathol Exp Neurol 36:570–575, 1977.
Erve JCL, Amarnath V, Graham D, et al: Carbon disulfide and N,N-diethyldithiocarbamate generate thiourea cross-links on erythrocyte
spectrin. Chem Res Toxicol 11:544–549, 1998a.
Erve JCL, Amarnath V, Sills RC, et al: Characterization of a valine-lysine
thiourea cross-link on rat globin produced by carbon disulfide or N,Ndiethyldithiocarbamate in vivo. Chem Res Toxicol 11:1128 – 1136,
1998b.
Federal Register: Principles of Neurotoxicity Risk Assessment. Environmental Protection Agency Final Report, vol 59, no 158. Washington,
DC: U.S. Government Printing Office, 1994, pp 42360–42404.
Ferraz HB, Bertolucci PH, Pereira JS, et al: Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese
intoxication. Neurology 38:550–553, 1988.
Filley CM, Kelly JP: Alcohol- and drug-related neurotoxicity. Curr Opin
Neurol Neurosurg 6:443–447, 1993.
Fishburne PM, Abelson HI, Cisin I: National Household Survey on Drug
Abuse: National Institute of Drug and Alcohol Abuse Capsules,
1982. Washington, DC: Department of Health and Human Services,
1983.
Flores G, Buhler DR: Hemolytic properties of hexachlorophene and related
chlorinated biphenols. Biochem Pharmacol 23:1835–1843, 1974.
Co
py
rig
hte
dM
ate
ria
l
Asanuma M, Hirata H, Cadet JL: Attenuation of 6-hydroxydopamine nigrostriatal lesions in superoxide dismutase transgenic mice. Neuroscience 85:907–917, 1998.
Atchison WD, Hare MF: Mechanisms of methylmercury-induced neurotoxicity. FASEB J 8:622–629, 1994.
Auer RN, Benveniste H: Hypoxia and related conditions, in Graham DI,
Lantos PL (eds): Greenfield’s Neuropathology, 6th ed. New York:
Arnold, 1997, pp 263–314.
Bachurin SO, Shevtzove EP, Lermontova NN, et al: The effect of dithiocarbamates on neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and on mitochondrial respiration chain. Neurotoxicology 17:897–903, 1996.
Bakir F, Damluji SF, Amin-Zaki L, et al: Methylmercury poisoning in Iraq.
Science 181:230–241, 1973.
Beal MF: Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 31:119–130,
1992.
Beal MF: Aging, energy, and oxidative stress in neurodegenerative diseases.
Ann Neurol 38:357–366, 1995.
Beal MF: Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol 44:S110–S114, 1998.
Becking GC, Boyes WK, Damstra T, et al: Assessing the neurotoxic potential of chemicals: A multidisciplinary approach. Environ Res 61:164–
175, 1993.
Behnke M, Eyler F, Conlon M, et al: Incidence and description of structural brain abnormalities in newborns exposed to cocaine. J Pediatr
132:291–294, 1998.
Benjamin JT, Platt C: Is universal screening for lead in children indicated?
An analysis of lead results in Augusta, Georgia in 1997. J Med Assoc
Georgia 88:24–26, 1999.
Benowitz NL: Clinical pharmacology of nicotine. Annu Rev Med 37:21–
32, 1986.
Bensadoun JC, Mirochnitchenko O, Innouye M, et al: Attenuation of 6OHDA-induced neurotoxicity in glutathione peroxidase transgenic
mice. Eur J Neurosci 10:3231–3236, 1998.
Besser R, Kramer G, Thumler R, et al: Acute trimethyltin limbic-cerebellar syndrome. Neurology 37:945–950, 1987.
Bouldin TW, Goines ND, Bagnell CR, Krigman MR: Pathogenesis of
trimethyltin neuronal toxicity: Ultrastructural and cytochemical observations. Am J Pathol 104:237–249, 1981.
Bouldin TW, Samsa G, Earnhardt TS, et al: Schwann cell vulnerability to
demyelination is associated with internodal length in tellurium neuropathy. J Neuropathol Exp Neurol 47:41–47, 1988.
Brouillet E, Jenkins BG, Hyman BT, et al: Age-dependent vulnerability of
the striatum to the mitochondrial toxin 3-nitropropionic acid. J Neurochem 60:356–359, 1993.
Burbacher TM, Sackett GP, Mottet NK: Methylmercury effects on the social behavior of Macaca fascicularis. Neurotoxicol Teratol 12:65–71,
1990.
Calne DB, Langston JW, Martin WR, et al: Positron emission tomography
after MPTP: Observations relating to the cause of Parkinson’s disease.
Nature 317:246–248, 1985.
Cammer W, Moore CL: The effect of hexachlorophene on the respiration
of brain and liver mitochondria. Biochem Biophys Res Commun
46:1887–1894, 1972.
Cavanagh JB: The significance of the “dying-back” process in experimental and human neurological disease. Int Nat Rev Exp Pathol 7:219–
267, 1964.
Chasnoff IJ, Burns WJ, Schnoll SH, et al: Cocaine use in pregnancy.
N Engl J Med 313:666–669, 1985.
Chaudry, V, Cornblath, DR: Wallerian degeneration in human nerves: Serial electrophysiological studies. Muscle Nerve 15:687 – 693, 1992.
Cheung MK, Verity MA: Experimental methyl mercury neurotoxicity: Locus of mercurial inhibition of brain protein synthesis in vivo and in
vitro. J Neurochem 44:1799–1808, 1985.
Choi DW: Glutamate neurotoxicity and diseases of the nervous system.
Neuron 1:623–634, 1988.
559
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
560
5/1/01
12:26 PM
Page 560
UNIT 4 TARGET ORGAN TOXICITY
Hollmann M, Heinemann S: Cloned glutamate receptors. Annu Rev Neurosci 17:31–108, 1994.
Hugon J, Ludolph A, Roy DN, et al: Studies on the etiology and pathogenesis of motor neuron diseases: II. Clinical and electrophysiologic
features of pyramidal dysfunction in macaques fed Lathyrus sativus
and IDPN. Neurology 38:435–442, 1988.
Ikonomidou C, Bittigau P, Ishimaru MJ, et al: Ethanol-induced apoptotic
neurodegeneration and fetal alcohol syndrome. Science 287:1056 –
1060, 2000.
Jerian SM, Sarosy GA, Link CJ Jr, et al: Incapacitating autonomic neuropathy precipitated by Taxol. Gynecol Oncol 51:277–280, 1993.
Johnson DJ, Graham DG, Amarnath V, et al: Release of carbon disulfide
is a contributing mechanism in the axonopathy produced by N,N-diethyldithiocarbamate. Toxicol Appl Pharmacol 148:288 – 296, 1998.
Johnston MV, Goldstein GW: Selective vulnerability of the developing
brain to lead. Curr Opin Neurol 11:689–693, 1998.
Kaku DA, Lowenstein DH: Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 113:821–
827, 1990.
Kesson CM, Baird AW, Lawson DH: Acrylamide poisoning. Postgrad Med
J 53:16–17, 1977.
Kinney HK, Armstrong DD: Perinatal neuropathology, in Graham DI, Lantos PL (eds): Greenfield’s Neuropathology, 6th ed. New York: Arnold,
1997, pp 535–599.
Klivenyi P, Clair D, Wermer M, et al: Manganese superoxide dismutase
overexpression attenuates MPTP toxicity. Neurobiol Dis 5:253–258,
1998.
Kniesel U, Wolburg H: Tight junctions of the blood-brain barrier. Cell Mol
Neurobiol 20:57–76, 2000.
Koehnle TJ, Brown A: Slow axonal transport of neurofilament protein in
cultured neurons. J Cell Biol 144:447–458, 1999.
Krasavage WJ, O’Donoghue JL, DiVincenzo GD, et al: The relative neurotoxicity of MnBk, n-hexane, and their metabolites. Toxicol Appl
Pharmacol 52:433–441, 1980.
Kuopio AM, Marttila RJ, Helenius H, et al: Changing epidemiology of
Parkinson’s disease in southwestern Finland. Neurology 52:302–308,
1999.
Kurland LT: Epidemiological investigations of neurological disorders in the
Mariana islands, in Pemberton J (ed): Epidemiology Reports on Research and Teaching. Oxford and New York: Oxford University Press,
1963, pp 219–223.
Kurland LT, Faro SN, Siedler J: Minamata disease. World Neurol 1:370–
395, 1960.
Kurth MC, Kurth JH: Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson’s disease. Am J Med Genet 48:166–168, 1993.
Lam G-W, DiStefano V: Characterization of carbon disulfide binding in
blood and to other biological substances. Toxicol Appl Pharmacol
86:235–242, 1986.
Langston JW, Forno LS, Tetrud J, et al: Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605,
1999.
Langston JW, Irwin I: MPTP: Current concepts and controversies. Clin
Neuropharmacol 9:485–507, 1986.
LeBel CP, Ali SF, Bondy SC: Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain. Toxicol Appl Pharmacol 112:161–165, 1992.
Letzel S, Lang CJ, Schaller KH, et al: Longitudinal study of neurotoxicity
with occupational exposure to aluminum dust. Neurology 54:997 –
1000, 2000.
Lichensteiger W, Ribary U, Schlumpf M, et al: Prenatal adverse effects of
nicotine on the developing brain, in Boer GJ, Feenstra MGP, Mirmiran M, et al (eds): Progress in Brain Research. Vol 73. Amsterdam:
Elsevier, 1988, pp 137–157.
Liou HH, Tsai MC, Chen CJ, et al: Environmental risk factors and Parkinson’s disease: A case-control study in Taiwan. Neurology 48:1583–
1588, 1997.
Co
py
rig
hte
dM
ate
ria
l
Freilich RJ, Byrne E: Alcohol and drug abuse. Curr Opin Neurol Neurosurg 5:391–395, 1992.
Funk KA, Liu CH, Higgins RJ, et al: Avian embryonic brain reaggregate
culture system. II. NTE activity discriminates between effects of a single neuropathic or nonneuropathic organophosphorus compound exposure. Toxicol Appl Pharmacol 124:159–163, 1994.
Gehlbach SH, Williams WA, Perry LD, et al: Green-tobacco sickness: An
illness of tobacco harvesters. JAMA 229:1880–1883, 1974.
Genter MB, Szkal-Quin G, Anderson CW, et al: Evidence that pyrrole formation is a pathogenetic step in -diketone neuropathy. Toxicol Appl
Pharmacol 87:351–362, 1987.
George EB, Glass JD, Griffin JW: Axotomy-induced axonal degeneration
is mediated by calcium influx through ion-specific channels. J Neurosci 15:6445–6452, 1995.
Gilbert SG, Rice DC: Low-level lifetime lead exposure produces behavioral toxicity (spatial discrimination reversal) in adult monkeys. Toxicol Appl Pharmacol 91:484–490, 1987.
Giros B, Jaber SR, Wightman RM, et al: Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612, 1996.
Glass JD, Brushart TM, George EB, et al: Prolonged survival of transected
fibers in C57BL/Ola mice is intrinsic characteristic of the axon. J Neurocytol 22:311–321, 1993.
Goldberger ME, Murray M: Recovery of function and anatomical plasticity after damage to the adult and neonatal spinal cord, in Cotman CW
(ed): Synaptic Plasticity. New York: Guilford Press, 1985, pp 77–110.
Goodrum JF: Role of organotellurium species in tellurium neuropathy. Neurochem Res 23:1313–1319, 1998.
Gorell JM, Johnson CC, Rybicki BA, et al: Occupational exposure to manganese copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology 20:239–247, 1999.
Gorell JM, Johnson CC, Rybicki BA, et al: The risk of Parkinson’s disease
with exposure to pesticides, farming, well water and rural living. Neurology 59:1346–1350, 1998.
Grafstein B: Axonal transport: Function and mechanisms, in Waxman SG,
Kocsis JD, Stys PK (eds): The Axon: Structure, Function, and Pathophysiology. New York: Oxford University Press, 1995, pp 185–199.
Graham DG, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14:633–643, 1978.
Graham DG, Amarnath V, Valentine WM, et al: Pathogenetic studies of
hexane and carbon disulfide neurotoxicity. CRC Crit Rev Toxicol 25:
91–112, 1995.
Graham DG, Tiffany SM, Bell WR Jr, Gutknecht WF: Autoxidation versus covalent binding of quinones as the mechanism of toxicity of
dopamine 6-hydroxydopamine and related compounds for C1300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653, 1978.
Griffin JW, Anthony DC, Fahnestock KE, et al: 3,4-Dimethyl-2,5-hexanedione impairs the axonal transport of neurofilament proteins. J Neurosci 4:1516–1526, 1984.
Griffin JW, Hoffman PN, Clark AW, et al: Slow axonal transport of neurofilament proteins: Impairment by ,-iminodipropionitrile administration. Science 202:633–635, 1978.
Griffin JW, Price DL: Proximal axonopathies induced by toxic chemicals,
in Spencer PS, Schaumburg HH (eds): Experimental and Clinical Neurotoxicology. Baltimore: Williams & Wilkins, 1980, pp 161–178.
Harris CH, Gulati AK, Friedman MA, et al: Toxic neurofilamentous axonopathies and fast axonal transport: V. Reduced bidirectional vesicle
transport in cultured neurons by acrylamide and glycidamide. J Toxicol Environ Health 42:343–456, 1994.
Harry GJ, Goodrum JF, Bouldin TW, et al: Tellurium-induced neuropathy:
Metabolic alterations associated with demyelination and remyelination in rat sciatic nerve. J Neurochem 52:938–945, 1989.
Herning R, King D, Better W, et al: Neurovascular deficits in cocaine
abusers. Neuropsychopharmacology 21:110–118, 1999.
Hoffman PN, Lasek RJ: The slow component of axonal transport: Identification of major structural polypeptides of the axon and their generality among mammalian neurons. J Cell Biol 66:351–366, 1975.
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
12:26 PM
Page 561
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
neurobehavioral screening methods: V. Results of chemical testing.
Neurotoxicology 18:969–1055, 1997c.
Mullick FG: Hexachlorophene toxicity: Human experience at the AFIP. Pediatrics 51:395–399, 1973.
Mulugeta S, Ciavarra RP, Maney RK, et al: Three subpopulations of fast
axonally transported retinal ganglion cell proteins are differentially
trafficked in the rat optic pathway. J Neurosci Res 59:247–258, 2000.
Myers JE, Macun I: Acrylamide neuropathy in a South African factory: An
epidemiologic investigation. Am J Indust Med 19:487–493, 1991.
Myers RR, Mizisin AP, Powell HC, et al: Reduced nerve blood flow in
hexachlorophene neuropathy: Relationship to elevated endoneurial
pressure. J Neuropathol Exp Neurol 41:391–399, 1982.
Needleman HL: Childhood lead poisoning. Curr Opin Neurol 7:187–190,
1994.
Needleman HL, Gatsonis CA: Low-level lead exposure and the IQ of children. A meta-analysis of modern studies. JAMA 263:673–678, 1990.
Nixon RA: Dynamic behavior and organization of cytoskeleton proteins in
neurons: Reconciling old and new findings. Bioessays 20:798–807,
1998.
Nixon RA, Sihag RK: Neurofilament phosphorylation: A new look at regulation and function. TINS 14:501–506, 1991.
Nunn PB, Seelig M, Zagoren JC, et al: Stereospecific acute neurotoxicity
of “uncommon” plant amino acids linked to human motor system diseases. Brain Res 410:375–379, 1987.
Olney JW: Neurotoxicity of excitatory amino acids, in McGeer EG, Olney
JW, McGeer PL (eds): Kainic Acid as a Tool in Neurobiology. New
York: Raven Press, 1978, pp 95–122.
O’Shea KS, Kaufman MH: The teratogenic effect of acetaldehyde: Implications for the study of fetal alcohol syndrome. J Anat 128:65–76,
1979.
Padilla S, Atkinson MB, Breuer AC: Direct measurement of fast axonal organelle transport in the sciatic nerve of rats treated with acrylamide.
J Toxicol Environ Health 39:429–445, 1993.
Pardridge WM: Blood-brain barrier biology and methodology. J Neurovirol 5:556–569, 1999.
Parent A: Carpenter’s Human Neuroanatomy, 9th ed. Baltimore: Williams
& Wilkins, 1996, pp 131–198.
Penny DG: Acute carbon monoxide poisoning: Animal models: A review.
Toxicology 62:123–160, 1990.
Perl TM, Bedard L, Kosatsky T, et al: An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N Engl
J Med 322:1775–1780, 1990.
Perlstein MA, Attala R: Neurologic sequelae of plumbism in children. Clin
Pediatr 5:292–298, 1966.
Pham-Dinh D, Popot JL, Boespflug-Tanguy O, et al: Pelizaeus-Merzbacher
disease: A valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. Proc Natl Acad Sci USA 88:
7562–7566, 1991.
Plum F, Posner JB: Neurobiologic essentials, in Smith LH Jr, Thier SO
(eds): Pathophysiology: The Biological Principles of Disease.
Philadelphia: Saunders, 1985, pp 1009–1036.
Polymerpoulos MH, Lavedan C, Leroy E, et al: Mutation in the alphasynuclein gene identified in families with Parkinson’s disease. Science
276:2045–2047, 1997.
Purves DC, Garrod IJ, Dayan AD: A comparison of spongiosis induced in
the brain by hexachlorophene, cuprizone, and triethyl tin in the
Sprague-Dawley rat. Hum Exp Toxicol 10:439–444, 1991.
Pyle SJ, Graham DG, Anthony DC: Dimethylhexanedione impairs the
movement of neurofilament protein subunits, NFM and NFL, in the
optic system. Neurotoxicology 15:279–286, 1994.
Quarles RH, Farrer RG, Yim SH: Structure and function of myelin, an extended and biochemically modified cell surface membrane, in Juurlink
BHJ, Devon RM, Doucette JR, et al. (eds): Cell Biology and Pathology of Myelin: Evolving Biological Concepts and Therapeutic Approaches. New York: Plenum Press, 1997, pp 1–12.
Qiu J, Cai D, Filbin MT: Glial inhibition of nerve regeneration in mature
mammalian CNS. Glia 29:166–174, 2000.
Co
py
rig
hte
dM
ate
ria
l
Lipton RB, Apfel SC, Dutcher JP, et al: Taxol produces a predominantly
sensory neuropathy. Neurology 39:368–373, 1989.
Lipton SA, Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622, 1994.
Liu Y, Fechter LD: Comparison of the effects of trimethyltin on the intracellular calcium levels in spiral ganglion cells and outer hair cells.
Acta Otolaryngol 116:417–421, 1996.
Llorens J, Dememes D, Sans A: The behavioral syndrome caused by 3,3iminodipropionitrile and related nitriles in the rat is associated with
degeneration of the vestibular sensory hair cells. Toxicol Appl Pharmacol 123:199–210, 1993.
Lotharius J, O’Malley KL: The parkinsonian-inducing drug 1-methyl-4phenylpyridinium triggers intracellular dopamine oxidation. J Biol
Chem 275:38581–38588, 2000.
Lotti M, Moretto A, Capodicasa E, et al: Interactions between neuropathy
target esterase and its inhibitors and the development of polyneuropathy. Toxicol Appl Pharmacol 122:165–171, 1993.
Lucey JF, Hibbard E, Behrman RE, et al: Kernicterus in asphyxiated newborn rhesus monkeys. Exp Neurol 9:43–58, 1964.
Ludolf AC, He F, Spencer PS, et al: 3-Nitropropionic acid: Exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci
18:492–498, 1991.
Ludolf AC, Seelig M, Ludolf A, et al: 3-Nitropropionic acid decreases cellular energy levels and causes neuronal degeneration in cortical explants. Neurodegeneration 1:155–161, 1992.
Lunn ER, Perry VH, Brown MC, et al: Absence of Wallerian degeneration
does not hinder regeneration in peripheral nerve. Eur J Neurosci
1:27–33, 1989.
Lyon MF, Ogunkolade BW, Brown MC, et al: A gene affecting Wallerian
nerve degeneration maps distally on mouse chromosome 4. Proc Nat
Acad Sci USA 90:9717–9720, 1993.
Malmfors T: The effects of 6-hydroxydopamine on the adrenergic nerves
as revealed by fluorescence histochemical method, in Malmfors T,
Thoenen H (eds): 6-Hydroxydopamine and Catecholaminergic Neurons. Amsterdam: North-Holland, 1971, pp 47–58.
Marshall JF, Drew MC, Neve KA: Recovery of function after mesotelencephalic dopaminergic injury in senescence. Brain Res 259:249–260,
1983.
Martenson CH, Sheetz MP, Graham DG: In vitro acrylamide exposure alters growth cone morphology. Toxicol Appl Pharmacol 131:119–129,
1995.
Marty MS, Atchison WD: Pathways mediating Ca2 entry in rat cerebellar granule cells following in vitro exposure to methyl mercury. Toxicol Appl Pharmacol 147:319–330, 1997.
Meldrum B: Excitatory amino acid antagonists as potential therapeutic
agents, in Jenner P (ed): Neurotoxins and Their Pharmacological Implications. New York: Raven Press, 1987, pp 33–53.
Miller DB: Neurotoxicity of the pesticidal carbamates. Neurobehav Toxicol Teratol 4:779–787, 1982.
Mitsuishi K, Takahashi A, Mizutani M, et al: Beta,beta-iminodipropionitrile toxicity in normal and congenitally neurofilament-deficient Japanese quails. Acta Neuropathol 86:578–581, 1993.
Monuki ES, Lemke G: Molecular biology of myelination, in Waxman SG,
Kocsis JD, Stys PK (eds): The Axon: Structure, Function, and Pathophysiology. New York: Oxford University Press, 1995, pp 144–163.
Morell P, Toews AD, Wagner M, et al: Gene expression during telluriuminduced primary demyelination. Neurotoxicology 15:171 – 180,
1994.
Moretta A: Promoters and promotion of axonopathies. Toxicol Lett 112:
17–21, 2000.
Moser VC, Becking GC, Cuomo V, et al.: The IPCS collaborative study on
neurobehavioral screening methods. III. Results of proficiency studies. Neurotoxicology 18:939–946, 1997a.
Moser VC, Becking GC, Cuomo V, et al: The IPCS collaborative study on
neurobehavioral screening methods: IV. Control data. Neurotoxicology 18:947–967, 1997b.
Moser VC, Becking GC, Cuomo V, et al: The IPCS collaborative study on
561
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
562
5/1/01
12:26 PM
Page 562
UNIT 4 TARGET ORGAN TOXICITY
HH (eds): Experimental and Clinical Neurotoxicology. Baltimore:
Williams & Wilkins, 1980, pp 356–373.
Snow BJ, Vingerhoets FJ, Langston JW, et al: Pattern of dopaminergic loss
in the striatum of humans with MPTP induced parkinsonism. J Neurol Neurosurg Psychiatry 68:313–316, 2000.
Spencer PS: Doxorubicin and related anthracyclines, in Spencer PS,
Schaumburg HH (eds): Experimental and Clinical Neurotoxicology.
New York: Oxford University Press, 2000, pp 529–533.
Spencer PS, Nunn PB, Hugon J, et al: Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237:517–522, 1987.
Spencer PS, Schaumburg HH: Central-peripheral distal axonopathy: The
pathology of dying-back polyneuropathies, in Zimmerman H (ed):
Progress in Neuropathology, vol 3. New York: Grune & Stratton, 1976,
pp 253–295.
Stewart PA: Endothelial vesicles in the blood-brain barrier: Are they related to permeability? Cell Mol Neurobiol 20:149–163, 2000.
Stoll G, Muller HW: Nerve injury, axonal degeneration and neural regeneration: Basic insights. Brain Pathol 9:313–325, 1999.
Stoltenburg-Didinger G, Spohr HL: Fetal alcohol syndrome and mental retardation: Spine distribution of pyramidal cells in prenatal alcohol exposed rat cerebral cortex. Brain Res 11:119–123, 1983.
Stone JD, Peterson AP, Eyer J, et al: Axonal neurofilaments are nonessential elements of toxicant-induced reductions in fast axonal transport:
Video-enhanced differential interference microscopy in peripheral
nervous system axons. Toxicol Appl Pharmacol 161:50–58, 1999.
Storch A, Kaftan A, Burkhardt K, et al: 6-Hydroxydopamine toxicity towards human SH-SY5Y dopaminergic neuroblastoma cells: Independent of mitochondrial energy metabolism. J Neural Transm 107:
281–293, 2000.
Takeuchi T, Morikawa H, Matsumoto H, et al: A pathological study of Minamata disease in Japan. Acta Neuropathol 2:40–57, 1962.
Tanner CM, Ottman R, Goldman SM, et al: Parkinson disease in twins: An
etiologic study. JAMA 281:341–346, 1999.
Teitelbaum JS, Zatorre RJ, Carpenter S, et al: Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels.
N Engl J Med 322:1781–1787, 1990.
Tilson HA: Neurobehavioral methods used in neurotoxicological research.
Toxicol Lett 68:231–240, 1993.
Toggas SM, Krady JK, Billingsley ML: Molecular neurotoxicology of
trimethyltin: Identification of stannin, a novel protein expressed in
trimethyltin-sensitive cells. Mol Pharmacol 42:44–56, 1992.
Valentine WM, Amarnath V, Amarnath K, et al: Carbon disulfide-mediated
protein cross-linking by N,N-diethyldithiocarbamate. Chem Res Toxicol 8:96–102, 1995.
Valentine WM, Amarnath V, Graham DG, et al: CS2 mediated cross-linking of erythrocyte spectrin and neurofilament protein: Dose response
and temporal relationship to the formation of axonal swellings. Toxicol Appl Pharmacol 142:95–105, 1997.
Valentine WM, Amarnath V, Graham DG, et al: Covalent cross-linking of
proteins by carbon disulfide. Chem Res Toxicol 5:254–262, 1992.
Valentine WM, Graham DG, Anthony DC: Covalent cross-linking of erythrocyte spectrin in vivo. Toxicol Appl Pharmacol 121:71 – 77,
1993.
Van de Kamp JL, Collins AC: Prenatal nicotine alters nicotinic receptor development in the mouse brain. Pharmacol Biochem Behav 47:889–
900, 1994.
Verity MA: Toxic disorders, in Graham DI, Lantos PL (eds): Greenfield’s
Neuropathology, 6th ed. New York: Arnold, 1997, pp 755–811.
Veronesi B, Jones K, Gupta S, et al: Myelin basic protein-messenger RNA
(MBP-mRNA) expression during triethyltin-induced myelin edema.
Neurotoxicology 12:265–276, 1991.
Volpe JJ: Effect of cocaine use on the fetus. N Engl J Med 327:399–407,
1992.
Wagner M, Toews AD, Morell P: Tellurite specifically affects squalene
epoxidase: Investigations examining the mechanism of telluriuminduced neuropathy. J Neurochem 64:2169–2176, 1995.
Co
py
rig
hte
dM
ate
ria
l
Readhead C, Schneider A, Griffiths I, et al: Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene
dosage. Neuron 12:583–595, 1994.
Reuhl KR, Chang LW: Effects of methylmercury on the development of
the nervous system: A review. Neurotoxicology 1:21–55, 1979.
Reuhl KR, Gilbert SG, Mackenzie BA, et al: Acute trimethyltin intoxication in the monkey (Macaca fascicularis). Toxicol Appl Pharmacol
79:436–452, 1985.
Riggs JE: Cigarette smoking and Parkinson’s disease: The illusion of a neuroprotective effect. Clin Neuropharmacol 15:88–99, 1992.
Riikonen R, Salonen I, Partanen K, et al: Brain perfusion SPECT and
MRI in foetal alcohol syndrome. Dev Med Child Neurol 41:652 –
659, 1999.
Rojas P, Klaassen CD: Metallothionein-I and -II knock-out mice are not
more sensitive than control mice to 1-methyl-1,2,3,6-tetrahydropyridine neurotoxicity. Neurosci Lett 273:113–116, 1999.
Ross JF, Lawhorn GT: ZPT-related distal axonopathy: Behavioral and electrophysiologic correlates in rats. Neurotoxicol Teratol 12:153 – 159,
1990.
Rothman SM, Olney JM: Glutamate and the pathophysiology of hypoxicischemic brain damage. Ann Neurol 19:105–111, 1986.
Roytta M, Horwitz SB, Raine CS: Taxol-induced neuropathy: Short-term
effects of local injection. J Neurocytol 13:685–701, 1984.
Roytta M, Raine CS: Taxol-induced neuropathy: Chronic effects of local
injection. J Neurocytol 15:483–496, 1986.
Rubin LL, Staddon JM: The cell biology of the blood-brain barrier. Annu
Rev Neurosci 22:11–28, 1999.
Sahenk Z, Barohn R, New P, Mendell JR: Taxol neuropathy: Electrodiagnostic and sural nerve biopsy findings. Arch Neurol 51:726–729, 1994.
Sahenk Z, Mendell JR: Pyrithione, in Spencer PS, Schaumburg HH (eds):
Experimental and Clinical Neurotoxicology. New York: Oxford University Press, 2000, pp 1050–1054.
Sahenk Z, Mendell JR: Axoplasmic transport in zinc pyridinethione neuropathy: Evidence for an abnormality in distal turn-around. Brain Res
186:343–353, 1980.
St. Clair MBG, Amarnath V, Moody MA, et al: Pyrrole oxidation and protein crosslinking are necessary steps in the development of -diketone
neuropathy. Chem Res Toxicol 1:179–185, 1988.
Sayre LM, Shearson CM, Wongmongkolrit T, et al: Structural basis of diketone neurotoxicity: Non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione a -diketone incapable of pyrrole formation. Toxicol Appl
Pharmacol 84:36–44, 1986.
Schiff PB, Horwitz SB: Taxol assembles tubulin in the absence of exogenous guanosine 59-triphosphate or microtubule-associated proteins.
Biochemistry 20:3242–3252, 1981.
Schionning JD, Larsen JO, Tandrup T, et al.: Selective degeneration of dorsal root ganglia and dorsal nerve roots in methyl mercury–intoxicated
rats: A stereological study. Acta Neuropathol 96:191–201, 1998.
Schlafer WW, Zimmerman U-JP: Calcium-activated protease and the regulation of the axonal cytoskeleton, in Elam JS, Cancalon P (eds): Advances in Neurochemistry. New York: Plenum Press, 1984, pp 261–
273.
Schnapp BJ, Reese TS: Dynein is the motor for retrograde axonal transport of organelles. Proc Natl Acad Sci USA 86:1548–1552, 1989.
Schoepfer R, Monyer H, Sommer B, et al: Molecular biology of glutamate
receptors. Prog Neurobiol 42:353–357, 1994.
Schutzman DL, Frankenfield-Chernicoff M, Clatterbaugh HE, et al: Incidence of intrauterine cocaine exposure in a suburban setting. Pediatrics 88:825–827, 1991.
Schwartz JH: The cytology of neurons, in Kandel ER, Schwartz JH, Jessell TM (eds): Principles of Neural Science. 3d ed. Norwalk, CT: Appleton & Lange, 1991, pp 37–48.
Seawright AA, Brown AW, Nolan CC, et al: Selective degeneration of
cerebellar cortical neurons caused by cycad neurotoxin, L-betamethylaminoalanine (L-BMAA), in rats. Neuropathol Appl Neurobiol
16:153–164, 1990.
Seppaleinen AM, Haltia M: Carbon disulfide, in Spencer PS, Schaumburg
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com
2996R_ch16_535-563
5/1/01
12:26 PM
Page 563
CHAPTER 16 TOXIC RESPONSES OF THE NERVOUS SYSTEM
Woods JR, Plessinger MA, Clark KE: Effect of cocaine on uterine blood
flow and fetal oxygenation. JAMA 257:957–961, 1987.
Wright SC, Zhong J, Zheng H, et al: Nicotine inhibition of apoptosis suggests a role in tumor production. FASEB J 7:1045–1051, 1993.
Yamamura Y: n-Hexane polyneuropathy. Folia Psychiatr Neurol 23:45–57,
1969.
Zhang J, Graham DG, Montine TS, et al: Enhanced N-methyl-4-tetrahydropyridine toxicity in mice deficient in CuZn-superoxide dismutase
or glutathione peroxidase. J Neuropathol Exp Neurol 59:53 – 61,
2000a.
Zhang J, Kravtsov V, Amarnath V, et al: Enhancement of dopaminergic neurotoxicity by the mercapturate of dopamine: Relevance to Parkinson’s
disease. J Neurochem 74:970–978, 2000b.
Co
py
rig
hte
dM
ate
ria
l
Wang L, Ho CL, Sun D, et al: Rapid movement of axonal neurofilaments
interrupted by prolonged pauses. Nature Cell Biol 2:137–141, 2000.
Williamson AM: The development of a neurobehavioral test battery for use
in hazard evaluations in occupational settings. Neurotoxicol Teratol
12:509–514, 1990.
Wilson JM, Kalasinsky K, Levey A, et al: Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med
2:699–703, 1996a.
Wilson JM, Levey AI, Bergeron C, et al: Striatal dopamine, dopamine
transporter, and vesicular monoamine transporter in chronic cocaine
users. Ann Neurol 40:428–439, 1996b.
Winneke G: Cross species extrapolation in neurotoxicology: Neurophysiological and neurobehavioral aspects. Neurotoxicology 13:15–25, 1992.
563
Copyright © 2001 by The McGraw-Hill Companies
Retrieved from: www.knovel.com