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LEARNING OBJECTIVES
Endothelial cells restrict the diffusion of microscopic objects (e.g., bacteria) and
large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing
the diffusion of small hydrophobic molecules (O2, CO2, hormones).
Cells of the barrier actively transport metabolic products such as glucose across
the barrier with specific proteins.
This "barrier" results from the selectivity of the tight junctions between endothelial
cells in CNS vessels that restricts the passage of solutes.
At the interface between blood and the brain, endothelial cells are stitched
together by these tight junctions, which are composed of smaller subunits,
frequently biochemical dimers, that are transmembrane proteins such as
occludin, claudins, junctional adhesion molecule (JAM), or ESAM.
Each of these transmembrane proteins is anchored into the endothelial cells by
another protein complex that includes zo-1 and associated proteins.
The bloodbrain barrier is composed of high-density cells restricting passage of
substances from the bloodstream much more than endothelial cells in capillaries
elsewhere in the body.
Many drugs are unable to pass the barrier, since 98 percent of them are heavier
than 500 daltons.
hormones generally do not penetrate the brain from the blood, except at the
'circumventricular organs
The blood-brain barrier is an effective way to protect the brain from common
infections.
as antibodies are too large to cross the blood-brain barrier, infections of the brain
when they do occur can be very serious and difficult to treat.
BBB BREAK
The BBB can be broken down by:
Hypertension (high blood pressure): high blood pressure opens the BBB
Development: the BBB is not fully formed at birth.
Hyperosmolitity: a high concentration of a substance in the blood can open
the BBB.
Microwaves: exposure to microwaves can open the BBB.
Radiation: exposure to radiation can open the BBB.
Infection: exposure to infectious agents can open the BBB.
Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the
BBB.
DISEASES AFFECTING THE BLOOD-BRAIN BARRIER
MENINGITIS
inflamed meninges disrupt blood-brain barrier
This increase penetration of various substances (including antibiotics) into the
brain
third generation cephalosporin or fourth generation cephalosporin is preferred.
MULTIPLE SCLEROSIS (MS)
Normally, nervous system is inaccessible for WBC due to BBB.
using MRI in an MS "attack," BBB has broken down in brain or spinal cord, T
lymphocytes crossing over and destroying the myelin.
MS is a disease of the blood-brain barrier.
The yellow ingredient turmeric, found in curry, has been shown to strengthen the
blood-brain barrier to resist attacks.
LATE-STAGE NEUROLOGICAL TRYPANOSOMIASIS (SLEEPING
SICKNESS)
Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in
which trypanosoma protozoa have crossed the blood-brain barrier.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
This, together with a generally muted immune environment within the brain itself,
protects the fragile neuronal network from the risk of damage that could ensue
from a full-blown immune response.
DRUGS TARGETING THE BRAIN
-The BBB is permeable to small and lipophilic (fat-loving) molecules (up to 800
atomic mass units), but larger molecules are not transported across unless there
is an active transport system available
Thus this is one of the stumbling blocks for drug delivery
An additional problem is the very effective drug efflux systems (P-gly-coprotein
P-gp ), which pump the drug back out of cells.
There are three main methods of transport across the BBB, none of which is
perfect .
Direct physical injection into site of interest.
Permeabilisation of tight junctions using either osmotic disruption or biochemical
opening (RMP-7 Alkermes, vasoactive compounds histamine).
Enhance transcytosis across the endothelial cells (transcytosis) to the
underlying brain cells can be achieved by increasing endocytosis (i.e.
internalisation of small extracellular molecules) by using liposomes or
nanoparticles loaded with the drug of interest. The uptake can be further
enhanced by specifically targeting the delivery system to receptors on the brain
endothelium surface that are capable of receptor mediated endocytosis.
This method is more selective than the tight junction disruption, especially if brain
specific targeting technology is used, but tends to be less efficient.
It also requires the discovery and development of receptor specific ligands, which
can be attached directly to the drug of interest or the drug delivery system itself.
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