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The blood-brain barrier to horseradish peroxidase under normal and experimental conditions

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Summary

This review paper deals with the transport of the protein tracer horseradish peroxidase across cerebral vessels under normal and various experimental conditions.

Electronmicroscopical investigations have revealed that, under normal conditions, a minor vesicular transfer of intravenously injected peroxidase occurs across the endothelium in segments of arterioles, capillaries and venules, especially in arterioles with a diameter about 15–30 μ. This normally occurring vesicular transport is susceptible to various experimental conditions. Thus the transfer of tracer increases when a hypertonic solution is injected into the internal carotid artery presumably due to vesicular transport.

Extensive acute hypertension of short duration also increases the vesicular transfer of peroxidase from blood to brain. Identical observations are obtained when the hypertension is evoked by intravenous injection of phentolamine and by electrically induced seizures.

During the postischemic period, one hour after release of the occlusion of an internal carotid artery in the Mongolian gerbil the vesicular transport of peroxidase is increased across the endothelium of cerebral vessels. The explanation may be release of serotonin from blood platelets during the occlusion. The serotonin could then increase the blood pressure locally in the brain resulting in an enhanced permeability.

Serotonin, after perfusion through the cerebral ventricular system, is also able to increase the normally occurring vesicular transfer. The most likely mechanism behind this phenomenon seems at the moment to be local hypertension evoked by serotonin-induced vasoconstriction of arterioles.

Finally, the enhanced vesicular transport across cerebral endothelium caused by porto-caval anastomosis is mentioned and the possible role of disturbances in the metabolism of amines as responsible for the extravasation is discussed.

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References

  • Adams, R. D., Foley, J. M.: The neurological disorders associated with liver disease. In: Metacbolic and Toxic Disease of the Nervous System, p. 242. Baltimore: Williams and Wilkins 1953

    Google Scholar 

  • Ames, A., Wright, R. L., Kowada, M., Thurston, J. M., Majno, G.: Cerebral ischemia. II. The no-reflow phenomenon. Amer. J. Path.52, 437–453 (1968)

    Google Scholar 

  • Arsénio-Nunes, M. L., Hossmann, K. A., Farkas-Bargeton, E.: Ultrastructural and histochemical investigation of the cerebral cortex of cat during and after complete ischemia. Acta neuropath. (Berl.)26, 329–344 (1973)

    Google Scholar 

  • Baltzan, M. A., Olszewski, J., Zervas, N.: Chronic porto-hepatic encephalopathy. J. Neuropath. exp. Neurol.16, 410–421 (1957)

    Google Scholar 

  • Bertler, Å., Falck, B., Rosengren, E.: The direct demonstration of a barrier mechanism in the brain capillaries. Acta pharmacol. (Kbh.)20, 321–327 (1963)

    Google Scholar 

  • Bodenheimer, T. S., Brightman, M. W.: A blood-brain barrier to peroxidase in capillaries surrounded by perivascular spaces. Amer. J. Anat.122, 249–267 (1968)

    Google Scholar 

  • Bolwig, T. G., Hertz, M. M., Holm-Jensen, J.: Blood-brain barrier permeability during electroshock seizures in the rat. Europ. J. clin. Invest.7, 95–100 (1977a)

    Google Scholar 

  • Bolwig, T. G., Hertz, M. M., Westergaard, E.: Acute hypertension —the cause of blood-brain barrier break-down during epileptic seizures. Europ. J. clin. Invest. (in press, 1977b)

  • Bolwig, T. G., Westergaard, E.: The permeability of the blood-brain barrier during electrically induced epileptic seizures. Proceedings from 8th Salzburg Conference on Cerebral Vascular Diseases, Salzburg, Sept. 1976

  • Brightman, M. W.: Extracellular movement and subsequent pinocytosis of exogenous proteins in the brain. Tex. Rep. Biol. Med.29, 245–247 (1971)

    Google Scholar 

  • Brightman, M. W., Hori, M., Rapoport, S. I., Reese, T. S., Westergaard, E.: Osmotic opening of tight junctions in cerebral endothelium. J. comp. Neurol.152, 317–326 (1973)

    Google Scholar 

  • Brightman, M. W., Klatzo, I., Olsson, Y., Reese, T. S.: The blood-brain barrier to proteins under normal and pathological conditions. J. Neurol. Sci.10, 215–239 (1970a)

    Google Scholar 

  • Brightman, M. W., Reese, T. S.: Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol.40, 648–677 (1969)

    Google Scholar 

  • Brightman, M. W., Reese, T. S., Feder, N.: Assessment with the electronmicroscope of the permeability to peroxidase of cerebral endothelium and epithelium in mice and sharks. In: Capillary Permeability, Alfr. Benzon Symp, Il, pp. 468–476. Copenhagen: Munksgaard 1970b

    Google Scholar 

  • Brightman, M. W., Reese, T. S., Olsson, Y., Klatzo, I.: Morphologic aspects of the blood-brain barrier to peroxidase in elasmobranchs. In: Progress in neuropathology, pp. 146–161. Ed.: H. M. Zimmerman. New York: Grune and Stratton (1971)

    Google Scholar 

  • Bulat, M., Supek, Z.: The penetration of 5-hydroxytryptamine through the blood-brain barrier. J. Neurochem.14, 265–271 (1967)

    Google Scholar 

  • Bulat, M., Supek, Z.: Passage of 5-hydroxytryptamine through the blood-brain barrier, its metabolism in the brain and elimination of 5-hydroxyindoleacetic acid from the brain tissue. J. Neurochem.15, 383–389 (1968)

    Google Scholar 

  • Bulle, P. H.: Effects of reserpine and chlorpromazine in prevention of cerebral edema and reversible cell damage. Proc. Soc. exp. Biol. (N.Y.)94, 553–556 (1957)

    Google Scholar 

  • Cavanagh, J. B., Kyu, M. H.: Type II Alzheimer change experimentally produced in astrocytes in the rat. J. neurol. Sci.12, 63–75 (1971a)

    Google Scholar 

  • Cavanagh, J. B., Kyu, M. H.: On the mechanism of type I Alzheimer abnormality in the nuclei of astrocytes. J. neurol. Sci.12, 241–261 (1971b)

    Google Scholar 

  • Chiang, J., Kowada, M., Ames, A., Wright, R. L., Majno, G.: Cerebral ischemia. III. Vascular changes. Amer. J. Path.52, 455–476 (1968)

    Google Scholar 

  • Clasen, R. A., Pandolfi, S., Hass, G. M.: Vital staining, serum albumin and the blood-brain barrier. J. Neuropath. exp. Neurol.29, 266–284 (1970)

    Google Scholar 

  • Cuypers, J., Matakas, F.: The effect of postischemic hyperemia on intracranial pressure and the no-reflow phenomenon. Acta neuropath. (Berl.)29, 73–84 (1974)

    Google Scholar 

  • Delorme, P., Gayet, J., Grignon, G.: Ultrastructural study on transcapillary exchanges in the developing telencephalon of the chicken: Brain Res.22, 269–283 (1970)

    Google Scholar 

  • Dodson, R. F., Aoyagi, M., Hartmann, A., Tagashira, Y.: Acute cerebral infarction and hypotension: an ultrastructural study. J. Neuropath. exp. Neurol.33, 400–407 (1974)

    Google Scholar 

  • Ehrlich, P.: Das Sauerstoff-Bedürfnis des Organismus. Eine farbenanalytische Studie. Berlin: A. Hirschwald 1885)

    Google Scholar 

  • Ehrlich, P.: Zur therapeutischen Bedeutung der substituirenden Schwefelsäuregruppe. Ther. Mh.1, 88–90 (1887)

    Google Scholar 

  • Feldberg, W., Myers, R. D.: Appearance of 5-hydroxytryptamine and an unidentified pharmacologically active lipid acid in effluent from perfused cerebral ventricles. J. Physiol. (Lond.)184, 837–855 (1966)

    Google Scholar 

  • Folbergrová, J., Ljunggren, B., Norberg, K., Siesjö, B. K.: Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates, and associated amino acids in the rat cerebral cortex. Brain Res.80, 265–279 (1974)

    Google Scholar 

  • Garcia, J. H., Cox, J. V., Hudgins, W. R.: Ultrastructure of the microvasculature in experimental cerebral infarction. Acta neuropath. (Berl.)18, 273–285 (1971)

    Google Scholar 

  • Giacomelli, F., Wiener, J., Spiro, D.: The cellular pathology of experimental hypertension. V. Increased permeability of cerebral arterial vessels. Amer. J. Path.59, 133–159 (1970)

    Google Scholar 

  • Graham, R., Karnovsky, M. J.: The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: Ultrastructural cytochemistry by a new technique. J. Histochem. Cytochem.14, 291–302 (1966)

    Google Scholar 

  • Hansson, H.-E., Johansson, B., Blomstrand, C.: Ultrastructural studies on cerebrovascular permeability in acute hypertension. Acta neuropath. (Berl.)32, 187–198 (1975)

    Google Scholar 

  • Hashimoto, P. H.: Intracellular channels as a route for protein passage in the capillary endothelium of the shark brain. Amer. J. Anat.134, 41–57 (1972)

    Google Scholar 

  • Hossmann, K.-A., Olsson, Y.: The effect of transient cerebral ischemia on the vascular permeability to protein tracers. Acta neuropath. (Berl.)18, 103–112 (1971a)

    Google Scholar 

  • Hossmann, K.-A., Olsson, Y.: Influence of ischemia on the passage of protein tracers across capillaries in certain blood-brain barrier injuries. Acta neuropath. (Berl.)18, 113–122 (1971b)

    Google Scholar 

  • Hossmann, K.-A., Zimmermann, V.: Resuscitation of the monkey brain after 1 h complete ischemia. I. Physiological and morphological observations. Brain Res.81, 59–74 (1974)

    Google Scholar 

  • Hösslin, C. von, Alzheimer, A.: Ein Beitrag zur Klinik und Pathologischen Anatomie der Westphal-Strümpellschen Pseudosklerose. Z. ges. Neurol. Psychiat.19, 1079–1087 (1972)

    Google Scholar 

  • Hudgins, W. R., Garcia, J. H.: Transorbital approach to the middle cerebral artery of the squirrel monkey: a technique for experimental cerebral infarction applicable to ultrastructural studies. Stroke1, 107–111 (1970a)

    Google Scholar 

  • Hudgins, W. R., Garcia, J. H.: The effect of electrocautery, atmospheric exposure, and surgical retraction on the permeability of the blood-brain barrier. Stroke1, 375–380 (1970b)

    Google Scholar 

  • Ito, U., Spatz, M., Walker, J. T., Klatzo, I.: Experimental cerebral ischemia in Mongolian gerbils. I. Light microscopic observations. Acta neuropath. (Berl.)32, 209–223 (1975)

    Google Scholar 

  • Karnovsky, M. J.: The ultrastructural basis of capillary permeability studied with peroxidase as a tracer. J. Cell Biol.35, 213–236 (1967)

    Google Scholar 

  • Klatzo, I., Ito, U., Go, G., Westergaard, E., Spatz, M., Walker, J. T.: Experimental brain edema in gerbils. In: Proc. VII. Int. Congress of Neuropathology, Budapest 1974, pp. 619–622. Amsterdam: Excerpta Medica 1975

    Google Scholar 

  • Klatzo, I., Miquel, J., Otenasek, R.: The application of fluorescein labeled serum proteins (FLSP) to the study of vascular permeability in the brain. Acta neuropath. (Berl.)2, 144–160 (1962)

    Google Scholar 

  • Kline, D. G., Doberneck, R. C., Chun B. K., Rutherford, B.: Encephalopathy in graded portocaval shunts. Ann. Surg.164, 1003–1012 (1966)

    Google Scholar 

  • Kowada, M., Ames, A., Majno, G., Wright, R. L.: Cerebral ischemia. An improved experimental method for study; cardiovascular effects and demonstration of an early vascular lesion in the rabbit. J. Neurosurg.28, 150–157 (1968)

    Google Scholar 

  • Lapham, L. W.: Cytologic and cytochemical studies of neuroglia. Amer. J. Path.41, 1–21 (1962)

    Google Scholar 

  • Laursen, H., Schröder, H., Westergaard, E.: The effect of portocaval anastomosis on the permeability to horseradish peroxidase of cerebral vessels of the rat. Acta path. microbiol. scand.83A, 266–268 (1975)

    Google Scholar 

  • Laursen, H., Westergaard, E.: The blood-brain barrier to horseradish peroxidase in rats with porto-systemic encephalopathy. J. Neuropath. appl. Neurobiol.3, 29–43 (1977)

    Google Scholar 

  • Loizou, L. A.: Uptake of monoamines into central neurones and the blood-brain barrier in the infant rat. Brit. J. Pharmacol.40, 800–813 (1970)

    Google Scholar 

  • Lorenzo, A. V., Hedley-Whyte, E. T., Eisenberg, J. M., Hsu, D. W.: Increased penetration of horseradish peroxidase across the blood-brain barrier induced by Metrazol seizures. Brain Res.88, 136–140 (1975)

    Google Scholar 

  • Martinez, A.: Electron microscopy in human hepatic encephalopathy. Acta neuropath. (Berl.)11, 82–86 (1968)

    Google Scholar 

  • Mossakowski, M. J.: Some aspects of the morphology and histochemistry of the cerebral changes in hepatic coma. In: Proc. V. int. Congress of Neuropathology and experimental Medicine, pp. 981–986. Amsterdam, New York, London, Milan, Tokyo, Buenos Aires: Excerpta Medica 1966

    Google Scholar 

  • Norenberg, M. D., Lapham, L. W.: The astrocyte response in experimental portalsystemic encephalopathy: an electron microscopic study. J. Neuropath. exp. Neurol.33, 422–435 (1974)

    Google Scholar 

  • Nørtved, J., Westergaard, E.: Transport of horseradish peroxidase across cerebral arterioles and venules. Anat. Rec.178, 428 (1974)

    Google Scholar 

  • Olsson, Y.: Blood-brain barrier to albumin in embryonic new born and adult rats. Acta neuropath. (Berl.)10, 117–122 (1968)

    Google Scholar 

  • Olsson, Y., Crowell, M., Klatzo, I.: The blood-brain barrier to protein tracers in focal cerebral ischemia and infarction caused by occlusion of the middle cerebral artery. Acta neuropath. (Berl.)18, 89–120 (1971)

    Google Scholar 

  • Olsson, Y., Hossmann, K.-A.: Fine structural localization of exudated protein tracers in the brain. Acta neuropath. (Berl.)16, 103–116 (1970)

    Google Scholar 

  • Olsson, Y., Klatzo, I., Sourander, P., Steinwall, O.: Blood-brain barrier to albumin in embryonic new born and adult rats. Acta neuropath. (Berl.)10, 117–122 (1968)

    Google Scholar 

  • Osterholm, H. L., Bell, J., Meyer, R., Pyenson, J.: Experimental effects of free serotonin on the brain and its relation to brain injury. Part 1: The neurological consequences of intracerebral serotonin injections. Part 2: Trauma-induced alterations in spinal fluid and brain. Part 3: Serotonin-induced cerebral edema. J. Neurosurg.31, 408–421 (1969)

    Google Scholar 

  • Rapoport, S. I.: Reversible opening of the blood-brain barrier by osmotic shrinkage of the cerebrovascular endothelium: opening of the tight junctions as related to carotid arteriography. In: Small vessel angiography (ed. Sadek H. Hilal), pp. 137–151. St. Louis: C. V. Mosby 1973

    Google Scholar 

  • Rapoport, S. I.: Target organ modification in pharmacology: Reversible osmotic opening of the blood-brain barrier by opening of tight junctions. In: Pharmacology and Pharmacokinetics (eds. T. Teorell, R. L. Dedrich, and P. G. Condliffe), pp. 241–251. New York: Plenum Press 1974

    Google Scholar 

  • Rapoport, S. I., Brightman, M. W., Reese, T. S.: Reversible osmotic opening of the blood-brain barrier by opening tight junctions of cerebrovascular endothelium. Biophysic Society's 17th Annual Meeting. Abstract 13:230a (1973)

    Google Scholar 

  • Rapoport, S. I., Hori, M., Klatzo, I.: Testing of a hypothesis for osmotic opening of the blood-brain barrier. Amer. J. Physiol.223, 323–331 (1972)

    Google Scholar 

  • Reese, T. S., Karnovsky, M. J.: Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol.34, 207–217 (1967)

    Google Scholar 

  • Scherega, H. A.: Protein structure, p. 305. New York: Academic Press 1961

    Google Scholar 

  • Spatz, M., Go, K. G., Klatzo, I.: The effect of ischemia on the brain uptake of14C glucose and14C sucrose. In: Pathology of cerebral microcirculation (ed. J. Cervós-Navarro), pp. 361–366. Berlin-New York: W. de Gruyter 1974

    Google Scholar 

  • Spiclmeyer, W.: Die histopathologische Zusammengehörigkeit der Wilsonschen Krankheit und der Pseudesklerose. Z. ges. Neurol. Psychiat.56/57 312 (1920)

    Google Scholar 

  • Suzuki, O., Takanohashi, M., Yagi, K.: Protective effect of dexamethasone on enhancement of blood-brain barrier permeability caused by electroconvulsive shock. Arzneimittel-Forsch. (Drug. Res.)26, 533–535 (1976)

    Google Scholar 

  • Tschirgi, R. D.: Protein complexes and the impermeability of the blood-brain barrier to dyes. Amer. J. Physiol.163, 756 (1950)

    Google Scholar 

  • Welch, K. M. A., Meyer, J. S., Kwant, S.: Estmation of levels of serotonin and 5-hydroxyindoles in whole blood by an autoanalytical procedure: observations on the blood-brain barrier. J. Neurochem.19, 1079–1087 (1972)

    Google Scholar 

  • Westergaard, E.: Transport of protein tracers across cerebral arterioles under normal conditions. In: Pathology of cerebral microcirculation (ed. J. Cervós-Navarro), pp. 218–227. Berlin-New York: W. de Gruyter 1974

    Google Scholar 

  • Westergaard, E.: Enhanced vesicular transport of exogenous peroxidase across cerebral vessels, induced by serotonin. Acta neuropath. (Berl.)32, 27–42 (1975a)

    Google Scholar 

  • Westergaard, E.: The effect of serotonin, norepinephrine and cyclic AMP on the blood-brain barrier. J. Ultrastruct. Res.50, 383 (1975b)

    Google Scholar 

  • Westergaard, E., Brightman, M. W.: Transport of proteins across normal cerebral arterioles. J. comp. Neurol.152, 17–44 (1973)

    Google Scholar 

  • Westergaard, E., Brøndsted, H. E.: The effect of acute hypertension on the vesicular transport of proteins in cerebral vessels. In: Proc. VII. Int. Congress of Neuropathology, Budapest 1974, pp. 619–622. Amsterdam: Excerpta Medica 1975.

    Google Scholar 

  • Westergaard, E., Deurs, B. van, Brøndsted, H. E.: Increased vesicular transfer of exogenous peroxidase across cerebral endothelium evoked by acute hypertension. In: Int. Symp. on Pathophysiological, Biochemical and Morphological Aspects of Cerebral Ischemia and Arterial Hypertension. Warsaw 1976 (in press)

  • Westergaard, E., Deurs, B. van, Brøndsted, H. E.: Increased vesicular transfer of horseradish peroxidase across cerebral endothelium, evoked by acute hypertension. Acta neuropath. (Berl.)37, 141–152 (1977)

    Google Scholar 

  • Westergaard, E., Go, K.-G., Klatzo, I., Spatz, M.: Enhanced vesicular transport of horseradish peroxidase across cerebral vessels induced by ischemia. In: Int. Symp. on Pathophysiological, Biochemical and Morphological Aspects of Cerebral Ischemia and Arterial Hypertension. Warsaw 1976a (in press)

  • Westergaard, E., Go, K.-G., Klatzo, I., Spatz, M.: Increased permeability of cerebral vessels to horseradish peroxidase induced by ischemia in Mongolian gerbils. Acta neuropath. (Berl.)35, 307–325 (1976b)

    Google Scholar 

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Westergaard, E. The blood-brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol 39, 181–187 (1977). https://doi.org/10.1007/BF00691695

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