Download Neurotoxicity

NERVOUS SYSTEM
TOXICOLOGY
DR. BASMA DAMIRI
173020
OUTLINE
• Nervous system anatomy and physiology
• Ways in which neurotoxic chemicals may impair nervous
system function
• Target of toxicity, Manifestations of neurotoxicity
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Membrane
Neuronopathies
Axonopathies
Myelinopathies
Neurotransmission-associated anomalities
• Prototypical toxicological agents
• Methylmercury
• Carbon disulfide
• Lead
• Nicotine
• Organochlorine insectides
• Organophosphorous insectides
• Venoms
Suggested Questions:
1.
What are the chemicals that act on the neuron and cause
disruption for it?
2.
What are peripheral neurotoxicants and how do they affect
neurons?
3.
Describe in details the function of blood brain barrier in brain
toxicity?
4.
What is the relationship between the nervous system and the
respiratory system (rule of anoxia in neurotoxicity)?
5.
What is the site effect of nicotine on the nervous system
(neurotoxicity)?
NERVOUS SYSTEM ANATOMY
NERVOUS SYSTEM ANATOMY
Nerve cell (neuron): functional unit
• Cell Body: makes proteins for all parts of neurone with
central nucleus
• Axons: long projections along which nerve impulses
travel rapidly
• Myelin sheath: fatty substance that insulates the axons
and speeds up conduction
• Post-synaptic membrane: nerve or muscle cell
Nervous system as a target organ
Structural damage to neuron
• Lead –
damages myelin sheath slowing nerve impulse
transmissions
• Mild symptoms – tiredness
• Severe cases – peripheral neuropathy producing muscle weakness,
often showing as ‘wrist drop’ or ‘foot drop’
• n-Hexane – causes swelling of axon and degeneration of axon
and myelin sheath
• Symptoms include muscular weakness and sensory motor loss
particularly to hands and feet
Nervous system as a target organ
• Structural damage to neuron
• Manganese – damages axon
• Symptoms resemble Parkinson’s disease with tremor
and difficulty in walking and speaking
• Mercury – damages the sensory nerves
• Symptoms include hearing, speech and vision
problems. Also tremors and shaking and psychiatric
disturbances
• Organo-metallics (e.g. methyl mercury and tetra
ethyl lead) – can readily reach the brain
• Symptoms include irritability, memory loss, convulsions
and psychiatric disturbances
Nervous system as a target organ
• Functional damage to nerve
• Organic solvents – act as CNS depressants
• High affinity for lipid rich tissues (e.g. myelin sheath) and absorb
into it causing swelling and impairing nerve impulse
transmission
• Acute narcotic and anaesthetic effects: drowsiness, loss of
feeling, unconsciousness, death
• Chronic effects: possible long-term damage to neurons
Nervous system as a target organ
• Functional damage to nerve
pesticides
–
depolarisation of axon is prolonged
• Organo-chlorine
polarisation
and
• Symptoms include tremors caused by nerves becoming hyper-
excitable
• Organo-phosphorous pesticides – interfere with chemical
transmission across the synapse
• Acetylcholine not hydrolysed by target cell enzymes leading to
reactivation of target cell
• Symptoms include excessive muscle contractions, convulsions and
paralysis
Response to neurotoxicants includes changes
in:
• Heart rate.
• Sensory perception
• Coordination
• Mood and many other physiological, behavioral, cognitive,
and emotional effect.
Ways in which neurotoxic chemicals may impair nervous
system function:
1.
Permanent damage since neurons do not usually regenerate.
2.
May disrupt the electrical impulse along the axon, either by
harming the myelin sheath or membrane integrity or by impairing
the synthesis function of proteins essential to axonal transport.
3.
Chemicals may also inhibit the neurotransmitters by blocking their
synthesis release or binding the receptors.
4.
General protein synthesis impairment may have an effect not only
on the neurotransmitters production, but also the production of
important enzymes which break down neurotransmitters when they
are no longer needed.
The anatomical and physiological features that makes
an axon a particular target for toxicants
1.
Blood Brain Barrier
a. Tight junctions of capillaries.
b. Oligodendrites-glial as a 2nd layer.
c. Astrocytes.
d. The chemical to go there has to be a lipophilic or
resemble a neurotransmitter.
e. Site of toxicity –Circumventricular organs- spinal and
autonomic ganglia. Less restrictive areas.
NERVOUS SYSTEM ANATOMY
BLOOD BRAIN BARRIER
Blood Brain barrier
• Selective barrier which protects most of brain against water
soluble toxins
• but permeable to lipid soluble toxins (e.g. organometals,
solvents)
• Matures 6 months after birth (consequence?)
Most
tissues
Blood brain
barrier
2- Importance of energy requirements of the
brain:
• High energy requirements the brain utilizes aerobic
glycolysis and, therefore, it is extremely sensitive to even
brief interruptions in the supply of oxygen ore glucose
• anything inhibits aerobic respiration as cyanide or
produces hypoxia such as CO will affect the brain and
leads to the early signs of dysfunction in the myocardium
and neurons.
• Anoxia: the relationship between the nervous system and
the respiratory system.
• The high metabolic rate of neurons requires that they be
well supplied with oxygen and a rapid waste transport
system.
• Damage to the NS under these conditions is a
combination of direct toxic effects on neurons and
secondary damage from systemic hypoxia or ischemia.
Examples of sensitivity of neurons to energy depletion.
• CO- may severely reduce the O2 supply to neurons and
eventually causes their death by anoxia.
Acute CO poisoning damage those structures in the CNS
that are most vulnerable to hypoxia (e.g. the neurons in
specific regions of basal ganglia and hippocampus, certain
layers of the cerebral cortex, and the cerebellar Purkinje
cells).
CO may also produce white matter damage. Systemic
hypotension is the best predictor of these lesions following
CO poisoning.
• H2S and Cn can irreversibly bind to cytochrome oxidase, an
essential component of the respiratory electron transport
chain, can affect autonomic nerves such as those controlling
breathing and heart rate which lead to death.
• 3-Nitropopronic acid (3-NP) naturally occurring mycotoxin 
irreversible inhibitor of succinate dehydrogenase that
produces ATP depletion in cerebral cortical explants and
associated wit motor disorders in livestock and humans that
have ingested contaminated food.
3-Obstacle of the space: the longer the axon,
the more likely to hit more places.
a.
b.
Neuropathy: When the neuronal cells body has lethally injured,
it degenerates, in a process called neuropathy no potential
of regeneration
Axonopathy: When the injury is on the level of the axon, it may
degenerate while the neuronal cell continuous to survive
Band of Bungner: if any part of the axon is damaged,
another elongation or repair could occur.
4.
Maintenance of an environment rich in lipids: Lipids
wrap around the axon (myelin sheath, Schwan
cells)- Exclude water-ions from the area-They have
particular lipids different than other cells- there are
certain toxicants that target these lipids.
5.
Transmission of information across extracellular
spaces –Synapse.
MANIFESTATIONS OF NEUROTOXICITY
MANIFESTATIONS OF NEUROTOXICITY
• Motor
• Sensory
• Autonomic
• Cognitive capabilities
Mechanism of neurotoxicity
Neuropathy
Neuropathy
 Ethanol and methanol
 Pb
 Mn
• The initial injury to neurons is
followed by apoptosis is or
necrosis leasing to permanent
loss of the neurons:
 Al
 As
 Bismuth
 6-amino nicotinamide
inhibition of NADPH
 CO
 CCl4
 Chloramphenicol
 CN
 Hg organic and inorganic
 Methyl bromide
 MPTP
 3-NP
 Phenytoin
 Quinine
 Streptomycin
 Thallium
 Trimethyltin: plasticizer,
antifungal agent, or pesticide.
can cause hearing loss
• The onset of neurotoxic problem may follow toxic
exposure for many years.
• The relationship between MPTP intoxication and
Parkinsonism has stimulated investigations into the role
that environmental and occupational exposure may play
in the pathogenesis of Parkinson’s disease.
• Herbicides , pesticides, metals risk factors
• Dithiocarbamate  paly important role
• Alzheimer’s disease  Al
MANIFESTATIONS OF NEUROTOXICITY
NEURONOPATHIES
• Doxorubicin  (adriamycin) A quinone-containing
anthracycline antibiotic, is one of the most effective
antimitotics in cancer chemotherapy.
• Clinical application is limited by acute and chronic
cardiotoxicity, injury to PNS.
• It can intercalate into grooves of DNA preventing
transcription
• If the blood-brain barrier is temporarily opened by the
use of mannitol, toxicity of Doxorubicin is ↑↑↑
• With injury in the neurons in the cortex and subcortical nuclei of
the brain
MERCURY
• Vapor from degassing in earth’s crust
• Methylated by microorganisms to CH3Hg
• CH3Hg is most significant form of Hg in terms of toxicity
from environmental exposure
• Bioconcentration in aquatic food chain
• 90 to 95% absorption in GIT
• Crosses placenta
MERCURY
METHYL MERCURY
• Neurotoxic effects lead to,
• Paresthesia
• Ataxia
• Neurasthenia
• Vision and hearing loss
• Coma and death
• Neurotoxic effects due to focal necrosis of neurons
MERCURY
METHYL MERCURY
• The critical or lowest level of observed adverse
health effect in adults is paresthesia
• The average long-term intake associated with
paresthesia calculated to be 300 μg/day for an
adult
• Poisoning therapy utilizes chelators such as
cysteine, penicillamine, thiol resins
• It is estimated that 3-4 million children live within a mile of
at least one of the 13000+ active hazardous waste sites in
USA.
• Clinical picture of Methg poisoning varies both with
severity of exposure and the age of individual at the time
of exposure.
• In adults, the most dramatic sites of injury are the neurons
of cereberall cortex whose massive degeneration results
in blindness and marked ataxia.
• In children, developmental disabilities, retardation, and
cognitive deficits occur.
LEAD
• Ubiquitous toxic metal
• Primary route of exposure is by ingestion
• Source is from lead-based paint, contaminated drinking
water, lead-glazed pottery
• Encephalopathy occurs at blood lead levels of 80-100
μg/dL
LEAD
• Symptoms of encephalopathy include lethargy, vomiting,
irritability, loss of appetite, and dizziness
• Progression of symptoms lead to ataxia, reduced level of
consciousness, which may progress to coma and death
• Recovery is often associated with life-long epilepsy, mental
retardation, optic neuropathy, blindness
LEAD
• Chronic toxicity affects PNS; Schwann cell degeneration
• Mechanisms of toxicity include,
• Impairment of cell-cell connections
• Alterations in neurotransmitter levels
• Disrupts calcium metabolism
Metaphyseal lead lines
Basophilic Stippling
• MPTP- a contaminant of synthetic heroin. Resemble
dopamine and acts as mitochondrial toxicant- high lipid
peroxidation- high ROS- release dopamine from the
vesicles
MANIFESTATIONS OF NEUROTOXICITY
Membrane:
• Chemicals that disrupt the membrane system can
seriously impair nervous system function.
• Solvents or cleaning agents like methanol,
trichloroethylene, tetrachloroethylene. They are lipophilic
and volatile
MANIFESTATIONS OF NEUROTOXICITY
AXONOPATHIES: dying –back neuropathy
• The primary site of toxicity is the axon itself. Microtubules
are usually the target.
• Degeneration of axon, surrounding myelin, but cell body
remains intact
• Irreversible in CNS, but reversible in PNS
• Caused by CS2, acrylamide, gold, organophosphorous
esters, chlordecone (Kepone), Dapsone, Li, metronidazole,
platinium,
CS2
• CS2: the most significant exposures of humans to CS2 have
•
•
•
•
•
occurred in the vulcan rubber and viscose rayon industry
distal axinopathy like n-hexane
Used in the production of viscose rayon, cellophane,
pesticides, as a solubilizer for waxes and oils
Exposure is predominantly occupational
Direct interaction with free amine and sulfhydryl groups
Microsomal activation to reactive sulfur intermediates that
bind macromolecules
Produce neuronal degeneration in CNS; in PNS produce
myelin swelling and fragmentation
MANIFESTATIONS OF NEUROTOXICITY
AXONOPATHIES
Gamma- Diketones
n-hexane Methyl n-butyl ketone
• Sensorimotor polyneuropathy
• Sensory numbness and paresthesia
• Distal nerves affected first (distal axon swelling in both motor or sensory
neurons)
• Clinical signs often delayed for 6-12+ months
• Axonal swelling and secondary demyelination
• 2,5-hexanedione is common toxic metabolite
• Gamma- Diketones react with amino groups on all proteins
forming pyrolle adducts, an important step in developing
axonopathy.
• Pyrolles are oxidized and cross-linking occurs between
microfilaments subunits.
• Neurofilaments accumulate in the distal axon, usually just
proximal to node of Rnvier, and forma massive axonal
swellings leading to reactions of myelin from the nodes.
Acrylamide
• Vinyl monomer used widely in water purification, paper
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•
•
•
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manufacturing, mining, and waterproofing.
It presents in many foods prepared at high temperatures.
PNS
Distal axonopathy  multiple axonal swellings
Large single dose or multiple smaller doses
Repeated dosing results in more proximal axonopathy
“dying back” process.
MANIFESTATIONS OF NEUROTOXICITY
MYELINOPATHIES
• Attack myelen sheath or Schwan cells and
oligodendritis
• Metals such as lead, thallium, and triethyltin can be
inhaled.
• Decreases the ability of conduction, slow down impulses.
• Increases the susceptibility to other damage.
• Thallium: causes vision loss
• Lead: impaired cognition
MYELINOPATHIES
• Intramyelinic edema
• Demyelination
• Remyelination in CNS occurs to a limited extent
• Remyelination in PNS done by Schwann cells
• Caused by amiodarone, disulfiram,Pb
MANIFESTATIONS OF NEUROTOXICITY
NEUROTRANSMISSION-ASSOCIATED ANOMALITIES
• Interruption of impulse transmission
• Blockade of transsynaptic communication
• Inhibition of neurotransmitter uptake
• Interference with second-messenger systems
Nicotine bind cholinergic receptor
amphetamines, methamphetamine alteration of
dopaminergic, serotonergic, and cholinergic systems
Cocaine  infarcts and hemorrhage
Atropine acts as adrenergic receptors, blocks
cholinergic receptors
Muscarine (mushroom) binds muscarinic receptor
(cholinergic )
NICOTINE
• Exposure from smoking
• Binds to nicotinic cholinergic receptors (low-dose)
stimulation; high-dose blocking
• Increase in HR
• Elevated BP
• Acute overdose leads to excessive stimulation of
nicotinic receptors leading to ganglionic paralysis
Neurotransmission associated toxicity
• Two main mechanisms of action:
1.
Binds to receptors or channels such as organo- chlorine
Insecticides.
2.
Binds to enzymes and prevents the breakdown of
neurotransmitters such as organo phosphorous insecticides (
OP) Parathion and carbamate.
Toxicants that bind to receptors or
channels:
1. DDT: Organochlorine insecticides
2. Cyclodienes: such as Chlordane, Kepone,
Mirex, endosulfan
3. Nicotine binds to acetylcholine receptor (Ach)
4. Ethanol
ORGANOCHLORINE INSECTICIDES
• DDT, lindane, dieldrin
• High lipid solubility, low degradation rate
• Persistence in environment, bioconcentration
and biomagnification in food chains
• Produce disturbances in ion transport across
axon leading to increased excitability and
seizures
1- DDT
cause tremors and seizure and increase sensitivity to
stimuli
1. Binds Na-ATPase act as a neurotransmitter.
2. Binds Ca-ATPase, Ca is essential for diffusion of
neurotransmitters to membrane. Inhibits Ca –
modulin.
Death occurs because of the continuous contraction
in human diaphragm- no breathing.
3. Inhibits norepinephrine function and manganese
which inhibits serotonin, norepinephrine, and
dopamine function
2. Cyclodienes: such as Chlordane, Kepone, Mirex,
endosulfan – act as antagonist for gama amino butyric
acid (GABA), a neurotransmitter.
3. Nicotine binds to acetylcholine receptor (Ach), nicotinic
receptors cause nicotine poisoning such as excitability,
nausea, and increased heart rate followed by muscle
relaxation, decreased heart rate, and sometimes coma
and death.
4. Ethanol: impairs axonal signal transmission by
disrupting the Na, and K channels.
Neurotransmission associated toxicity
• Two main mechanisms of action:
1.
Binds to receptors or channels such as organo- chlorine
Insecticides.
2.
Binds to enzymes and prevents the breakdown of
neurotransmitters such as organo phosphorous
insecticides ( OP) Parathion and carbamate.
Toxicants that bind to neurotransmitter enzymes
and prevent breakdown of neurotransmitters
• Anticholinesterase insecticides
• Organ phosphorous insecticide (OPs).
• Carbamate
OPS : chemical intermediate, flame retardants, fuel additives,
hydrolytic fluid, lubricants, pharmaceutical, plasticizers.
Pesticide and nerve agents
• Symptoms of carbamate toxicity similar to those of OPs
but of shorter duration or milder severity.
Pesticide Aging
• we are removing the acetyl group –after choline is removed away, two
alkyl groups are left on P. If one alkyl group was cleaved, the second
group will be hydrolyzed so slow (few days). No possibility of second
hydrolysis because of dealkylation. We have to regenerate the
enzyme.
• Second hydrolysis is very slow and takes days. The body will remake
the enzymes than to hydrolyze it.
• Aging will occur with ethyl (least likely to age), propyl or butyl (more
likely to age).
OPIDN - Organophosphate Induced Delayed Neuropathy
Some of OP compounds, such as tri-o-cresyl phosphate (TOCP) are
neuropathic and can cause a sever sensorimotor central peripheral
distal axonopathy called OPIDN without inducing cholinergic toxicity
 called also delayed neuropathy or delayed polyneuropathy
(OPIDP)
USA  contaminated alcohol, Morocco contaminated olive oil
• Clinical signs
• Ataxia and paralysis
• Develop 10 to 14 days after exposure
• Neuropathology
• Wallerian-type degeneration
• Mode of Action
• Inhibition of neurotoxic esterase (NTE) is generally predictive
Clinical signs related to excessive stimulation of
nicotinic and muscarinic receptors
1.
2.
3.
4.
5.
6.
7.
8.
9.
Muscle tremors
CNS effects
Respiratory paralysis (this is what causes death)
Salivation, Lacrimation, Urination, and Defecation
CNS signs
Bronchospasm
Bronchial secretions
Miosis
Bradycardia
OPIDN - Organophosphate Induced Delayed
Neuropathy
• Clinical signs
• Ataxia and paralysis
• Develop 10 to 14 days after exposure
• Neuropathology
• Wallerian-type degeneration
• Mode of Action
• Inhibition of neurotoxic esterase (NTE) is generally predictive
Chemical Treatment:
• 1. Atropine – NEVER give 2-PAM as hydrolysis occur.
• Hydrolysis:
• Acetylcholine> atropine> carbamate
• 1 sec
> min to hrs
• OP hydrolysis never occurs
ORGANOPHOSPHOROUS PESTICIDES
• Malathion, parathion, “nerve gases”
• Inhibits acetylcholinesterase (AChE) leading to
continuous stimulation
• Neurobehavioral, cognitive, neuromuscular
disturbances
• Intermediate syndrome
• Death from respiratory distress
VENOMS
ARACHNIDA
• Scorpions, spiders
• Contain low molecular weight proteins that affect ion
transport along axon
• Impairs action potential
• Symptoms include tachycardia, respiratory distress