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Other likely BBB functions possibly related to aging
Neurobiology of Aging, Vol. 9, p. 52. Pergamon Journals Ltd., 1988. Printed in the U.S.A.
0197-4580/88 $3.00 + .00
Other Likely BBB Functions Possibly Related to Aging WILLIAM OLDENDORF
Department of Neurology and Psychiatry UCLA School of Medicine, Los Angeles, CA 90024
In addition to selectively facilitating transport between blood and brain, the BBB appears to carry out other functions. It probably protects the brain from trophic peptides in blood. It also maintains a different electrolyte concentration in the neuronal environment relative to blood plasma. It also prevents the loss of locally produced neurotransmitters and modulator substances in brain. The cytoplasmic enzymes in brain capillary endothelial cells may also alter molecular structure on route between blood and brain. Any of these functions may be disturbed in the aging brain, but we do not understand them well enough to draw any conclusions as yet.
Mooradian, could fail in the aged. The BBB probably also serves to prevent the loss to blood which could act as an efficient sink for many neurotransmitters and modulator substances produced (or released) regionally. If there were no BBB these substances would be washed away and their local confinement would be impossible. For a regionally sustained level to be achieved, much more synthesis of the centrally produced substance would be required. Another BBB function which could be clinically relevant is the prevention of free entry into brain of peptide growth enhancers or inhibitors. Fluctuating levels of these substances in brain from changing levels in blood could cause havoc. Finally, the BBB could serve to keep out blood-born peptidases and proteinases which would interfere with brain's control of centrally produced labile proteins and peptides. Whatever the BBB's function is, it probably allows the creation of very stable levels of many substances in brain and allows some considerable independence from the levels of these substances in blood. Potassium, for example, is about 40% lower in concentration in brain extracellular fluid than in plasma and its normal concentration remains constant in the face of considerable plasma fluctuations. Injection in humans of hypertonic iodinated angiographic contrast agents disrupts the BBB transiently but it does not seem to alter brain function in any easily recognized way. This suggests that brief (a few minutes) of BBB disruption of the brain causes no malfunction and this, in turn, suggests that the functions of BBB are long term, perhaps regulating growth and other slowly changing processes.
THIS excellent review by Dr. Mooradian of the BBB and possible relationships to aging brings the reader up to date on this potentially important aspect of changing BBB function. Three aspects of BBB function are addressed in Dr. Mooradian's review: (1) exclusion of substances in blood, (2) selective transport of some substances into brain and (3) excretion of some endproducts of brain metabolism from brain. Of additional interest is the free transport of many lipophilic substances (largely of exogenous origin) which readily penetrate the BBB. An aspect of BBB function not addressed is the mechanism by which the capillary bed in brain becomes selectively permeable rather than generally permeable to all small molecules as found in non-brain capillaries. There is a growing body of evidence indicating that some source in brain (probably astrocytes) and probably by some humoral process induces nearby brain capillaries to undergo the structural changes which make them selectively permeable. Almost any adverse influence on brain (mechanical trauma, local heat, neoplasia and perhaps even aging) results in a " l o s s " of the BBB, meaning that the microcirculation in the abnormal area becomes generally permeable. If, indeed, the BBB is the result of some ongoing process of healthy astrocytes, the structural reversion of capillaries to those resembling non-neural capillaries in response to diverse adversities may simply respresent malfunctioning astrocytes which can no longer carry on their usual function of maintaining the BBB. It is conceivable that astrocytic malfunction due to aging could also cause partial loss of the BBB. In addition to becoming leaky, specific transport systems in the BBB, such as choline transport described by Dr.
Letters to the Editor We encourage our readers to respond to this review and associated peer commentaries in the form of formal " L e t t e r s to the Editor." Relatively short letters with a specific point or two are most appropriate. In all cases, the author of the original review or commentary will be given an opportunity to respond to the letter.
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0197-4580/88 $3.00 + .00
Other Likely BBB Functions Possibly Related to Aging WILLIAM OLDENDORF
Department of Neurology and Psychiatry UCLA School of Medicine, Los Angeles, CA 90024
In addition to selectively facilitating transport between blood and brain, the BBB appears to carry out other functions. It probably protects the brain from trophic peptides in blood. It also maintains a different electrolyte concentration in the neuronal environment relative to blood plasma. It also prevents the loss of locally produced neurotransmitters and modulator substances in brain. The cytoplasmic enzymes in brain capillary endothelial cells may also alter molecular structure on route between blood and brain. Any of these functions may be disturbed in the aging brain, but we do not understand them well enough to draw any conclusions as yet.
Mooradian, could fail in the aged. The BBB probably also serves to prevent the loss to blood which could act as an efficient sink for many neurotransmitters and modulator substances produced (or released) regionally. If there were no BBB these substances would be washed away and their local confinement would be impossible. For a regionally sustained level to be achieved, much more synthesis of the centrally produced substance would be required. Another BBB function which could be clinically relevant is the prevention of free entry into brain of peptide growth enhancers or inhibitors. Fluctuating levels of these substances in brain from changing levels in blood could cause havoc. Finally, the BBB could serve to keep out blood-born peptidases and proteinases which would interfere with brain's control of centrally produced labile proteins and peptides. Whatever the BBB's function is, it probably allows the creation of very stable levels of many substances in brain and allows some considerable independence from the levels of these substances in blood. Potassium, for example, is about 40% lower in concentration in brain extracellular fluid than in plasma and its normal concentration remains constant in the face of considerable plasma fluctuations. Injection in humans of hypertonic iodinated angiographic contrast agents disrupts the BBB transiently but it does not seem to alter brain function in any easily recognized way. This suggests that brief (a few minutes) of BBB disruption of the brain causes no malfunction and this, in turn, suggests that the functions of BBB are long term, perhaps regulating growth and other slowly changing processes.
THIS excellent review by Dr. Mooradian of the BBB and possible relationships to aging brings the reader up to date on this potentially important aspect of changing BBB function. Three aspects of BBB function are addressed in Dr. Mooradian's review: (1) exclusion of substances in blood, (2) selective transport of some substances into brain and (3) excretion of some endproducts of brain metabolism from brain. Of additional interest is the free transport of many lipophilic substances (largely of exogenous origin) which readily penetrate the BBB. An aspect of BBB function not addressed is the mechanism by which the capillary bed in brain becomes selectively permeable rather than generally permeable to all small molecules as found in non-brain capillaries. There is a growing body of evidence indicating that some source in brain (probably astrocytes) and probably by some humoral process induces nearby brain capillaries to undergo the structural changes which make them selectively permeable. Almost any adverse influence on brain (mechanical trauma, local heat, neoplasia and perhaps even aging) results in a " l o s s " of the BBB, meaning that the microcirculation in the abnormal area becomes generally permeable. If, indeed, the BBB is the result of some ongoing process of healthy astrocytes, the structural reversion of capillaries to those resembling non-neural capillaries in response to diverse adversities may simply respresent malfunctioning astrocytes which can no longer carry on their usual function of maintaining the BBB. It is conceivable that astrocytic malfunction due to aging could also cause partial loss of the BBB. In addition to becoming leaky, specific transport systems in the BBB, such as choline transport described by Dr.
Letters to the Editor We encourage our readers to respond to this review and associated peer commentaries in the form of formal " L e t t e r s to the Editor." Relatively short letters with a specific point or two are most appropriate. In all cases, the author of the original review or commentary will be given an opportunity to respond to the letter.
52