|
Certain substances are not taken up by the brain tissue to
the same extent by other tissues. No substances is totally excluded. This
BBB has anatomical and physiological substances.
Anatomical Consideration:
Earlier studies suggested that the barrier is located at the
cerebral vasculature. Some suggested that BBB resides in the complete
enclosure of the cerebral capillary by glial end feet. Another view
attributed BBB only to the small extra cellular space. In 1960s experiments
demonstrated that cerebral endothelial cells are held together by tight
junctions that form a continuous occluding zone between adjacent cells.
Single layered cerebral capillary endothelial cells
connected with adjacent endothelial cells by tight junction represent the
anatomical substrates for the barrier.
In addition the cerebral capillary endothelial cell
possesses a greater number and volume of mitochondria than the general
body capillary as well as a number of enzymes specific to the brain
capillaries.
As compared to general capillary wall, the brain capillary
wall has smaller fenestrations.
In addition the brain capillary wall is reinforced with as
pericytes & astrocytic foot process.
The electrical resistance of the cell membrane differs from
that of general capillary wall. The tight capillaries of the brain have
high impedance and low ionic permeability whereas the reverse is true for
the leaky body capillary.
A functionally similar BBB is present in all vertebrates and
is essentially mature at birth. Maturation of the astrocytic process
coincides with the development of the fully functioning barrier.
Circum-ventricular organs (area postrema, subfornical organs & median
eminence) are devoid of the type of capillaries that constitute the
barrier.
Physiological Considerations:
Water soluble (electrolytes) substances both small and
large, cross the barrier with great difficulty whereas lipid soluble
substances (alcohol , narcotics and anticonvulsants) pass with ease.
Compounds bound to plasma protein (steroid, thyroxin) take longer than
the unbound form. Greater the lipid solubility, greater is the passage.
Specified transport systems are responsible for passage of
certain water soluble but biologically important substances such as
D-Glucose, Phenylamine. There are seven important systems.
|
Transport system
|
Substrate
|
|
1. Hexose
|
D-Glucose
|
|
2. Mono carbolic acid
|
Lactate
|
|
3. Neutral amino acids
|
Phenylamine
|
|
4. Basic amino acids
|
Arginine
|
|
5. Amine
|
Choline
|
|
6. Nucleoside
|
Adenosine
|
|
7. Purine
|
Adenine
|
Functions of BBB:
In addition to protecting the brain from toxic substances,
it controls the neuronal environment by regulating the movement of
biologically important molecules in and out of the cerebral extracellular
space across the capillaries. Two basic mechanisms are available to
control the extracellular environment.
1. Sodium transport system controls the concentration of
NACL2 in the extracellular fluid and also induces small volume of fluid
to enter the brain . K+ pump located on the anti luminal surface of the
cerebral capillary controls the movement of the ion from brain to blood.
2. The second mechanism is located at the Blood-CSF barrier
(choroid plexus). The choroidal ependyma and cerebral capillary endothelium
also act as miniature kidneys as they have transport systems capable of
moving substances out of the ventricular fluid and cerebral extra
cellular fluid respectively back into blood.
Carbohydrates is the primary fuel for brain. Hexose
transport system is at its highest capacity at the BBB and recognizes
only the Dform, can easily supply the glucose requirements. Insulin is
not required
Two transport systems operate across BB for neutral amino
acids. In addition there are separate carriers for choline, adenosine and
adenine.
Pathological alterations of BBB:
1. Metabolic disorders:
There exists a competition for carrier sites by the
transported amino acids. When the plasma concentration of one of the
competing aminoacids increases, its movement across enhances. This
competition priority develops in hepatic failure. During fasting,
lactate, 3 hydroxyhydrate and acetoacetate transport is increased.
2. Epilepsy:
Acute rise in BP, and blood flow that follows a seizure is
associated with increase in the number and volume of pinocytic vesicles
of the brain capillaries with deranged tight cell junctions are
responsible for increased movement of normally excluded substances. BBB
is restored in about 1 hr. Reduction of BP, steroids and pentobarbitones
appear to protect and restore BBB.
3. Cerebrovascular disorders:
As a general rule, there is break down of BBB with
extravasations of serum proteins and the development of vasogenic
cerebral edema. Stretching and weakening of tight junctions and
development of pinocytic vesicles during acute hypertension are assumed
to be the cause. In ischemia, the first opening occurs immediately after
recirculation and is due to the vasodilatation associated with reactive
hyperemia. The second is delayed and related to pathological changes in
cerebral tissue.
4. Brain tumors:
In primary brain tumors, the abnormal capillaries are found
in the more malignant tumors and have cellular fenestrations, wide
junctions, pinocytotic vesicles and in folding of luminal surfaces. The
metastatic tumors have capillary properties similar to that of the
derivative tissue. These changes form the basis of higher uptake of
isotopes and contrast media. The adverse effect of vasogenic cerebral
edema which often accompanies, on brain metabolism and functions is due
primarily to alterations in the neuronal environment, collapse of micro
vessels by edema fluid, tissue hypoxia and the cellular effect of the
extravasating serum proteins. Radiotherapy can also alter BBB, changes
may be seen many years after exposure.
5. CNS infections:
There is selective break down of BBB similar to that occurs
in some tumors. The leucocytes pass through BBB and there is some
derangement of the glucose transport. When treatment becomes effective,
the antibiotics have greater difficulty to penetrate as BBB return to
normal.
Clinical applications:
BBB can be transiently opened to the passage of
macromolecules by osmotic shock by injecting a hyperosmotic agent
(mannitol) to the brain to deliver therapeutics such as methotrexate,
antibiotics (gentamycin) etc.
Circumventing the BBB is also used with various success;
intrathecal, intraventricular instillations are occasionally used.
Neural transplantation is another approach still in the
experimental stage with autonomic ganglion transplants. These grafts have
properties of nonneural capillaries and their extracellular spaces are in
continuity with adjacent normal brain tissue and serve as a portal for
the entry of wide variety of restricted substances such as peptides,
hormones and immuno globulins. Once these substances gain access to the
ECF of transplant, they pass into the ECF of adjacent brain.
Knowledge of drug permeability help in clinical practice.
Antibiotics such as sulfas and erythromycin have a high degree of
penetration, whereas penicillin and tetracyclines have limited
capability.
|
