Blood Brain Barrier:


Dr. A. Vincent Thamburaj,

Neurosurgeon, Apollo Hospitals, Chennai , India.

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


1. Hexose


2. Mono carbolic acid


3. Neutral amino acids


4. Basic amino acids


5. Amine


6. Nucleoside


7. Purine


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.


























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