Download The Nervous System

The Nervous System
• The human nervous system can be
divided into two parts: the central nervous
system (CNS) and the peripheral nervous
system (PNS)
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Central Nervous System
Drugs that affect the CNS can:
•Selectively relieve pain
•Reduce fever
•Suppress disordered movement
•Induce sleep or arousal
•Reduce appetite
•Allay the tendency to vomit
•Be used to treat anxiety, depression,
schizophrenia, Parkinson’s Disease,
Alzheimer’s Disease, epilepsy, migraine, etc.
How do drugs work in the CNS?
• “A central underlying concept of
neuropharmacology is that drugs that
influence behavior and improve the
functional status of patients with
neurological or psychiatric diseases act by
enhancing or blunting the effectiveness of
specific combinations of synaptic
transmitter actions.”
Blood Brain Barrier (BBB)
• A physiological mechanism that alters the
permeability of brain capillaries, so that some
substances, such as certain drugs, are
prevented from entering brain tissue, while other
substances are allowed to enter freely.
• The separation of the brain, which is bathed in a
clear cerebrospinal fluid, from the bloodstream.
The cells near the capillary beds external to the
brain selectively filter the molecules that are
allowed to enter the brain, creating a more
stable, nearly pathogen-free environment.
Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain
barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial)
cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier
towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the
'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fatsoluble molecules that have crossed into the cells
Blood-Brain-Barrier
• Oxygen, glucose, and white blood cells
are molecules that are able to pass
through this barrier. Red blood cells
cannot.
Blood Brain Barrier
• The blood-brain barrier (abbreviated BBB) is
composed of endothelial cells packed tightly in
brain capillaries that more greatly restrict
passage of substances from the bloodstream
than do endothelial cells in capillaries elsewhere
in the body.
• Processes from astrocytes surround the
epithelial cells of the BBB providing biochemical
support to the epithelial cells.
• The BBB should not be confused with the bloodcerebrospinal fluid barrier (BCB), a function of
the choroid plexus.
History of the BBB
• The existence of such a barrier was first noticed
in experiments by Paul Ehrlich in the late-19th
century. Ehrlich was a bacteriologist who was
studying staining, used for many studies to make
fine structures visible. Some of these dyes,
notably the aniline dyes that were then popular,
would stain all of the organs of an animal except
the brain when injected. At the time, Ehrlich
attributed this to the brain simply not picking up
as much of the dye.
• However, in a later experiment in 1913, Edwin
Goldmann (one of Ehrlich's students) injected
the dye into the spinal fluid of the brain directly.
• He found that in this case the brain would
become dyed, but the rest of the body remained
dye-free. This clearly demonstrated the
existence of some sort of barrier between the
two sections of the body.
History of the BBB
• At the time, it was thought that the blood vessels
themselves were responsible for the barrier, as
there was no obvious membrane that could be
found.
• It was not until the introduction of the scanning
electron microscope to the medical research
fields in the 1960s that this could be
demonstrated. The concept of the blood-brain
(then termed hematoencephalic) barrier was
proposed by Lina Stern in 1921.
What is the purpose of the BBB?
• The blood-brain barrier protects the brain from the
many chemicals flowing around the body.
• For example, many bodily functions are controlled by
hormones, which are detected by receptors on the
plasma membranes of targeted cells throughout the
body.
• The secretion of many hormones are controlled by
the brain, but these hormones generally do not
penetrate the brain from the blood, so in order to
control the rate of hormone secretion effectively,
there are specialized sites where neurons can
"sample" the composition of the circulating blood.
• At these sites, the blood-brain barrier is 'leaky';
these sites include three important
'circumventricular organs', the subfornical
organ, the area postrema and the organum
vasculosum of the lamina terminalis (OVLT).
• The blood-brain barrier is also an effective way
to protect the brain from common infections.
Thus infections of the brain are very rare;
however, as antibodies are too large to cross
the blood-brain barrier, when infections of the
brain do occur they can be very serious and
difficult to treat.
How does the BBB affect the design of
therapeutic agents?
• Mechanisms for drug targeting in the brain involve
going either "through" or "behind" the BBB.
• Modalities for drug delivery through the BBB entail
disruption of the BBB by osmotic means,
biochemically by the use of vasoactive substances
such as bradykinin, or even by localized exposure
to high intensity focused ultrasound (HIFU).
• The potential for using BBB opening to target
specific agents to brain tumors has just begun to
be explored.
The Blood Brain Barrier
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