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In/. I Radrarmn Onndu@ BwI Pbyc Vol. 19. pp. I58 I - I587 Printed in the U.S.A. 411 rights reserved.
??Special Feature
EFFECTS OF IONIZING RADIATION ON THE BLOOD BRAIN BARRIER PERMEABILITY TO PHARMACOLOGICALLY ACTIVE SUBSTANCES TOM&
Institute of Experimental
TRNOVEC,
ZOLTAN
ALLAY
AND
STEFAN
BEZEK
Pharmacology, Slovak Academy of Sciences. CS-842 16 Bratislava, Czechoslovakia
Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultra-structural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physicochemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding lo-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. Either an increase or a decrease of BBB permeability, or both, occurring in a certain time sequence, was observed. The mechanism of hyperpermeability after irradiation is not fully understood, but the activation of vesicular transport offers one possible explanation. Even less understood is the mechanism of decreased permeability. The response of the BBB to ionizing radiation is most probably nonspecific and its nature may be assumed to be similar to its responses to other physical or chemical noxious factors. Blood brain barrier, Ionizing radiation, Pharmacologically
active substances.
Knowledge of the blood brain barrier (BBB) has increased immensely during the last 3 decades, mostly because of the development of methods used for the study of its structure and function (25). Recent data on the morphology and physiology of the BBB were reviewed by several authors, and the interested reader can consult, among others, the following issues: methods for quantifying the transport ofdrugs across brain barrier systems (3 I), general aspects of the BBB structure and functions ( 12-14, 42, 46) teleological aspects of the BBB (57), ultrastructure of the BBB (21, 26, 34). and passage of endogenous substances and xenobiotics across the BBB (30, 56). Although the reader will have basic knowledge on the structure and function of the BBB, we present a brief overview of essential data. The site of the barrier is the endothelium of all intracerebral vessels, except those in certain high permeability regions. In the body, brain excepting, the capillaries are freely permeable to all small
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In/. I Radrarmn Onndu@ BwI Pbyc Vol. 19. pp. I58 I - I587 Printed in the U.S.A. 411 rights reserved.
??Special Feature
EFFECTS OF IONIZING RADIATION ON THE BLOOD BRAIN BARRIER PERMEABILITY TO PHARMACOLOGICALLY ACTIVE SUBSTANCES TOM&
Institute of Experimental
TRNOVEC,
ZOLTAN
ALLAY
AND
STEFAN
BEZEK
Pharmacology, Slovak Academy of Sciences. CS-842 16 Bratislava, Czechoslovakia
Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultra-structural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physicochemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding lo-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. Either an increase or a decrease of BBB permeability, or both, occurring in a certain time sequence, was observed. The mechanism of hyperpermeability after irradiation is not fully understood, but the activation of vesicular transport offers one possible explanation. Even less understood is the mechanism of decreased permeability. The response of the BBB to ionizing radiation is most probably nonspecific and its nature may be assumed to be similar to its responses to other physical or chemical noxious factors. Blood brain barrier, Ionizing radiation, Pharmacologically
active substances.
Knowledge of the blood brain barrier (BBB) has increased immensely during the last 3 decades, mostly because of the development of methods used for the study of its structure and function (25). Recent data on the morphology and physiology of the BBB were reviewed by several authors, and the interested reader can consult, among others, the following issues: methods for quantifying the transport ofdrugs across brain barrier systems (3 I), general aspects of the BBB structure and functions ( 12-14, 42, 46) teleological aspects of the BBB (57), ultrastructure of the BBB (21, 26, 34). and passage of endogenous substances and xenobiotics across the BBB (30, 56). Although the reader will have basic knowledge on the structure and function of the BBB, we present a brief overview of essential data. The site of the barrier is the endothelium of all intracerebral vessels, except those in certain high permeability regions. In the body, brain excepting, the capillaries are freely permeable to all small
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requests
molecules (
