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Choroid Plexus Recovery After Transient Forebrain Ischemia: Role of Growth Factors and Other Repair Mechanisms

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Abstract

1. Transient forebrain ischemia in adult rats, induced by 10 min of bilateral carotid occlusion and an arterial hypotension of 40 mmHg, caused substantial damage not only to CA-1 neurons in hippocampus but also to epithelial cells in lateral ventricle choroid plexus.

2. When transient forebrain ischemia was followed by reperfusion (recovery) intervals of 0 to 12 hr, there was moderate to severe damage to many frond regions of the choroidal epithelium. In some areas, epithelial debris was sloughed into cerebrospinal fluid (CSF). Although some epithelial cells were disrupted and necrotic, their neighbors exhibited normal morphology. This patchy response to ischemia was probably due to regional differences in reperfusion or cellular metabolism.

3. Between 12 and 24 hr postischemia, there was marked restoration of the Na+, K+, water content, and ultrastructure of the choroid plexus epithelium. Since there was no microscopical evidence for mitosis, we postulate that healthy epithelial cells either were compressed together on the villus or migrated from the choroid plexus stalk to more distal regions, in order to “fill in gaps” along the basal lamina caused by necrotic epithelial cell disintegration.

4. Epithelial cells of mammalian choroid plexus synthesize and secrete many growth factors and other peptides that are of trophic benefit following injury to regions of the cerebroventricular system. For example, several growth factors are upregulated in choroid plexus after ischemic and traumatic insults to the central nervous system.

5. The presence of numerous types of growth factor receptors in choroid plexus allows growth factor mediation of recovery processes by autocrine and paracrine mechanisms.

6. The capability of choroid plexus after acute ischemia to recover its barrier and CSF formation functions is an important factor in stabilizing brain fluid balance.

7. Moreover, growth factors secreted by choroid plexus into CSF are distributed by diffusion and convection into brain tissue near the ventricular system, e.g., hippocampus. By this endocrine-like mechanism, growth factors are conveyed throughout the choroid plexus–CSF–brain nexus and can consequently promote repair of ischemia-damaged tissue in the ventricular wall and underlying brain.

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REFERENCES

  • Baird, A., and Bohlen, P. (1990). Fibroblast growth factors. In Sporn, M. B., and Roberts, A. B. (eds.), Peptide Growth Factors and Their Receptors, Springer, Berlin, pp. 369-418.

    Google Scholar 

  • Baskin, D. G., Wilcox, B. J., Figlewicz, D. P., and Dorsa, D. M. (1988). Insulin and insulin-like growth factors in the CNS. TINS 11:107-111.

    Google Scholar 

  • Bloch, B., Normand, E., Kovesdi, I., and Bohlen, P. (1992). Expression of the HBNF (heparin-binding neurite-promoting factor) gene in the brain of fetal, neonatal and adult rat: an in situ hybridization study. Dev. Brain Res. 70:267-278.

    Google Scholar 

  • Bohannon, N. J., Corp, E. S., Wilcox, B. J., Figlewicz, D. P., Dorsa, D. M., and Baskin, D. G. (1988). Localization of binding sites for insulin-like growth factor-I (IGF-I) in the rat brain by quantitative autoradiography. Brain Res. 444:205-213.

    Google Scholar 

  • Chalazonitis, A., Kalberg, J., Twardzik, D. R., Morrison, R. S., and Kessler, J. A. (1992). Transforming growth factor-β has neurotrophic actions on sensory neurons in vitro and is synergistic with nerve growth factor. Dev. Biol. 152:121-132.

    Google Scholar 

  • Chodobski, A., Szmydynger-Chodobska, J., Vannorsdall, M. D., Epstein, M. H., and Johanson, C. E. (1994). AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat. Reg. Peptides 53:123-129.

    Google Scholar 

  • Chodobski, A., Loh, Y. P., Corsetti, S., Szmydynger-Chodobska, J., Johanson, C. E., Lim, Y.-P., and Monfils, P. R. (1997). The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium. Mol. Brain Res. 48:67-72.

    Google Scholar 

  • Cortez, S., Johanson, C., Kuo-LeBlanc, V., Rodriguez-Wolf, M., Baird, A., Gonzalez, A. M., Seddon, A., and Stopa, E. G. (1995). Heparin-binding growth factors in control and Alzheimer choroids plexus. Soc. Neurosci. Abstr. 21:741.

    Google Scholar 

  • Cuevas, P., Cercellar, F., Reimers, D., Xiaobing, F., and Gimenez-Gallego, G. (1994). Immunohistochemical localization of basic fibroblast growth factor in choroid plexus of the rat. Neurol. Res. 16:310-312.

    Google Scholar 

  • Diaz-Ruiz, C., Perez-Thomas, R., Domingo, J., and Ferrer, I. (1993). Immunohistochemical localization of transforming growth factor-α in choroid plexus of the rat and chicken. Neurosci. Lett. 164:44-46.

    Google Scholar 

  • Endoh, M., Pulsinelli, W. A., and Wagner, J. A. (1994). Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor. Mol. Brain Res. 22:76-88.

    Google Scholar 

  • Esser, S., Wolburg, K., Wolburg, H., Breier, G., Kurzchalia, T., and Risau, W. (1998). Vascular endothelial growth factor induces endothelial fenestrations in vitro. J. Cell Biol. 140:947-959.

    Google Scholar 

  • Finch, C. E., Laping, N. J., Morgan, T. E., Nichols, N. R., and Pasinetti, G. M. (1993). TGF-β1 is an organizer of responses to neurodegeneration. J. Cell Biochem. 53:314-322.

    Google Scholar 

  • Finklestein, S. P., Apostolides, P. J., Caday, C. G., Prosser, J., Philips, M. F., and Klagsbrun, M. (1988). Increased basic fibroblast growth factor (bFGF) immunoreactivity at the site of focal brain wounds. Brain Res. 460:253-259.

    Google Scholar 

  • Flanders, K. C., Ren, R. F., and Lippa, C. F. (1998). Transforming growth factor-βs in neurodegenerative diseases. Prog. Neurobiol. 54:71-85.

    Google Scholar 

  • Garner, C., and Brown P. D. (1992). Two types of chloride channel in the apical membrane of rat choroid plexus epithelial cells. Brain Res. 591:137-145.

    Google Scholar 

  • Gillardon, F., Lenz, C., Kuschinsky, W., and Zimmerman, M. (1996). Evidence for apoptotic cell death in the choroid plexus following focal cerebral ischemia. Neurosci. Lett. 207:113-116.

    Google Scholar 

  • Glaumann, B., Glaumann, H., Berezersky, I., and Trump, B. (1977). Studies on cellular recovery from injury. II. Ultrastructural studies on the recovery of the pars convoluta of the proximal tubule of the rat kidney from temporary ischemia. Virchows Arch. B Cell Pathol. 24:1-18.

    Google Scholar 

  • Gospodarowicz, D., and Moran, J. S. (1975). Mitogenic effect of fibroblast growth factor on early passage cultures of human and murine fibroblasts. J. Cell Biol. 66:451-457.

    Google Scholar 

  • Holloway, L. S., Jr., and Cassin, S. (1972). Cerebrospinal fluid dynamics in the newborn dog during normoxia and hypoxia. Am. J. Physiol. 223:499-502.

    Google Scholar 

  • Hynes, M. A., Brooks, P. J., Van Wyk, J. J., and Lund, P. K. (1988). Insulin-like growth factor II messenger ribonucleic acids are synthesized in the choroid plexus of the rat brain. Mol. Endocrinol. 2:47-54.

    Google Scholar 

  • Ikeda, J., Mies, G., Nowak, T. S., Jr., Joo, F., and Klatzo, I. (1992). Evidence for increased calcium influx across the choroid plexus following brief ischemia of gerbil brain. Neurosci. Lett. 142:257-259.

    Google Scholar 

  • Johanson, C. E. (1989a). Ontogeny of the blood-brain barrier. In Neuwelt, E. (ed.), Implications of the Blood-Brain Barrier and Its Manipulation, Vol. 1. Basic Science Aspects, Plenum Press, New York, pp. 101-129.

    Google Scholar 

  • Johanson, C. E. (1989b). Potential for pharmacological manipulation of the blood-cerebrospinal fluid barrier. In Neuwelt, E. (ed.), Implications of the Blood-Brain Barrier and Its Manipulation, Vol. 1. Basic Sci. Aspects, Plenum Press, New York, pp. 223-260.

    Google Scholar 

  • Johanson, C. E. (1993). Tissue Barriers: Diffusion, bulk flow and volume transmission of proteins and peptides within the brain. In Audus, K. L., and Raub, T. J. (eds.), Pharmaceutical Biotechnology 5: Biological Barriers to Protein Delivery, Plenum, New York, pp. 467-486.

    Google Scholar 

  • Johanson, C. E. (1995). Ventricles and cerebrospinal fluid. In Michael Conn, P. (ed.), Neuroscience in Medicine, J. B. Lippincott, Philadelphia, pp. 171-196.

    Google Scholar 

  • Johanson, C. E. (1998). Arachnoid membrane, subarachnoid CSF and pia-glia. In Pardridge, W. M. (ed.), Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology, Cambridge University Press, Cambridge, pp. 259-269.

    Google Scholar 

  • Johanson, C. E., and Murphy, V. A. (1990). Acetazolamide and insulin alter choroid plexus epithelial cell [Na+], pH, and volume. Am. J. Physiol. 258:F1538-F1546.

    Google Scholar 

  • Johanson, C. E., and Woodbury, D. M. (1978). Uptake of C-14 urea by the in vivo choroid plexus cerebrospinal fluid-brain system: Identification of sites of molecular sieving by the choroid plexus of the rat. J. Physiol. (Lond.) 275:167-176.

    Google Scholar 

  • Johanson, C. E., Reed, D. J., and Woodbury, D. M. (1974). Active transport of sodium and potassium by the choroid plexus of the rat. J. Physiol. (Lond.) 241:359-372.

    Google Scholar 

  • Johnson, N. F., and Foulds, W. S. (1978). The effects of total acute ischemia on the structure of the rabbit retina. Exp. Eye Res. 27:45-59.

    Google Scholar 

  • Jung, W., Castren, E., Odenthal, M., Vande Woude, G. F., Ishii, T., Dienes, H.-P., Lindholm, D., and Schirmacher, P. (1994). Expression and functional interaction of hepatocyte growth factor-scatter factor and its receptor c-met in mammalian brain. J. Cell Biol. 126:485-494.

    Google Scholar 

  • Kawamata, T., Dietrich, W. D., Schaller, T., Gotts, J. E., Cocke, R. R., Benowitz, L. I., and Finklestein, S. P. (1997). Intracisternal basic fibroblast growth factor enhances functional recovery and upregulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc. Natl. Acad. Sci. USA 94:8179-8184.

    Google Scholar 

  • Klein, R., Martin-Zanca, D., Barbacid, M., and Parada, L. F. (1990). Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development 109:845-850.

    Google Scholar 

  • Klempt, N. D., Sirimanne, E., Gunn, A. J., Klempt, M., Singh, K., Williams, C., and Gluckman, P. D. (1992). Hypoxia-ischemia induces transforming growth factor β1 mRNA in the infant rat brain. Mol. Brain Res. 13:93-101.

    Google Scholar 

  • Knuckey, N. W., Preston, J., Palm, D., Epstein, M. H., and Johanson, C. E. (1993). Hydrocephalus decreases chloride efflux from the choroid plexus epithelium. Brain Res. 618:313-317.

    Google Scholar 

  • Knuckey, N. W., Palm, D., Primiano, M., Epstein, M. H., and Johanson, C. E. (1995). N-Acetylcysteine enhances hippocampal neuronal survival after transient brain ischemia in rats. Stroke 26:305-311.

    Google Scholar 

  • Knuckey, N. W., Finch, P., Palm, D. E., Primiano, M. J., Johanson, C. E., Flanders, K. C., and Thompson, N. L. (1996). Differential neuronal and astrocytic expression of transforming growth factor beta isoforms in rat hippocampus following transient forebrain ischemia. Mol. Brain Res. 40:1-14.

    Google Scholar 

  • Kozlowski, G. P. (1982). Ventricular route hypothesis and peptide-containing structures of the cerebroventricular system. In Rodriguez, E. M., and van Wimersma Greidanus, Ti. B. (eds.), Frontiers of Hormone Research, Vol. 9. Cerebrospinal Fluid (CSF) and Peptide Hormones, S. Karger, Basel, pp. 105-118.

    Google Scholar 

  • Lafond, R. E., Giammalvo, J. T., and Norkin, L. C. (1995). Relationship between expression of epidermal growth factor and simian virus 40 T antigen in a line of transgenic mice. Transgenic Res. 4:306-314.

    Google Scholar 

  • Lee, B. C. P., and Zimmer, J. (1978). Ventricular opacification after intravascular injections of contrast material. Radiology 128:647-649.

    Google Scholar 

  • Levine, S. (1987). Choroid plexus: Target for systemic disease and pathway to the brain. Lab. Invest. 56:231-233.

    Google Scholar 

  • Logan, A., Frautschy, S. A., Gonzalez, A.-M., and Baird, A. (1992a). A time course for the focal elevation of synthesis of basic fibroblast growth factor and one of its high-affinity receptors (flg) following a localized cortical brain injury. J. Neurosci. 12:3828-3837.

    Google Scholar 

  • Logan, A., Frautschy, S. A., Gonzalez, A.-M., Sporn, M. B., and Baird, A. (1992b). Enhanced expression of transforming growth factor β1 in the rat brain after a localized cerebral injury. Brain Res. 587:216-225.

    Google Scholar 

  • Maktabi, M. A., and Faraci, F. M. (1994). Endogenous angiotensin II inhibits production of cerebrospinal fluid during posthypoxemic reoxygenation in the rabbit. Stroke 25:1489-1494.

    Google Scholar 

  • Marmor, M., and Dalal, R. (1993). Irregular retinal and RPE damage after pressure-induced ischemia in the rabbit. Invest. Ophthalmol. Vis. Sci. 34:2570-2575.

    Google Scholar 

  • Michael, D. K., and Heisey, S. R. (1973). Effects of brain ventricular perfusion and hypoxia on CSF formation and absorption. Exp. Neurol. 41:769-772.

    Google Scholar 

  • Murphy, V. A., and Johanson, C. E. (1985). Adrenergic-induced enhancement of brain barrier system permeability to small nonelectrolytes: Choroid plexus versus cerebral capillaries. J. Cereb. Blood Flow Metab. 5:401-412.

    Google Scholar 

  • Nagahiro, S., Goto, S., Korematsu, K., Sumi, M., Takahashi, M., and Ushio, Y. (1994). Disruption of the blood-cerebrospinal fluid barrier by transient cerebral ischemia. Brain Res. 633:305-311.

    Google Scholar 

  • Nilsson, C., Lindvall-Axelsson, M., and Owman, C. (1992). Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res. Rev. 17:109-138.

    Google Scholar 

  • Nozaki, K., Finklestein, S. P., and Beal, M. F. (1993). Basic fibroblast growth factor protects against hypoxia-ischemia and NMDA neurotoxicity in neonatal rats. J. Cereb. Blood Flow Metab. 13:221-228.

    Google Scholar 

  • Ohta, S., Gido, G., and Siesjo, B. K. (1992). Influence of ischemia on blood-brain and blood-CSF calcium transport. J. Cereb. Blood Flow Metab. 12:525-528.

    Google Scholar 

  • Palm, D., Knuckey, N., Guglielmo, M., Watson, P., Primiano, M., and Johanson, C. (1995a). Choroid plexus electrolytes and ultrastructure following transient forebrain ischemia. Am. J. Physiol. 269:R73-R79.

    Google Scholar 

  • Palm, D. E., Knuckey, N. W., Primiano, M. J., Spangenberger, A. G., and Johanson, C. E. (1995b). Cystatin C, a protease inhibitor, in degenerating rat hippocampal neurons following transient forebrain ischemia. Brain Res. 691:1-8.

    Google Scholar 

  • Pollay, M. (1974). Transport mechanisms in the choroid plexus. Fed. Proc. 33:2064-2069.

    Google Scholar 

  • Pollay, M., Hisey, B., Reynolds, E., Tomkins, P., Stevens, F. A., and Smith, R. (1985). Choroid plexus Na+/K+-activated adenosine triphosphatase and cerebrospinal fluid formation. Neurosurgery 17:768-772.

    Google Scholar 

  • Preston, J. E., Sutherland, G., and Finsten, A. (1993). Three openings of the blood-brain barrier produced by forebrain ischemia in the rat. Neurosci. Lett. 149:75-78.

    Google Scholar 

  • Pulsinelli, W. A., Brierly, J. B., and Plum, F. (1982). Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann. Neurol. 11:491-498.

    Google Scholar 

  • Riegler, M., Sedivy, R., Sogukoglu, T., Cosentini, E., Bischof, G., Teleky, B., Feil, W., Schiessel, R., Hamilton, G., and Wenzl, E. (1997). Effect of growth factors on epithelial restitution of human colonic mucosa in vitro. Scand. J. Gastroenterol. 32:925-932.

    Google Scholar 

  • Schreiber, G., and Aldred, A. (1990). Pathophysiological aspects of plasma protein formation in the choroid plexus. In Johansson, B., Owman, C., and Widner, H. (eds.), Pathophysiology of the Blood-Brain Barrier, Elsevier, New York, pp. 89-102.

    Google Scholar 

  • Smith, Q. R., and Johanson, C. E. (1980). Effect of ouabain and potassium on ion concentrations in the choroidal epithelium. Am. J. Physiol. 238:F399-F406.

    Google Scholar 

  • Smith, Q. R., and Johanson, C. E. (1991). Chloride efflux from isolated choroid plexus. Brain Res. 562:306-310.

    Google Scholar 

  • Solem, M., Rawson, C., Lindburg, K., and Barnes, D. (1990). Transforming growth factor beta regulates cystatin C in serum-free mouse embryo (SFME) cells. Biochem. Biophys. Res. Commun. 172:945-951.

    Google Scholar 

  • Spector, R., and Johanson, C. E. (1989). The mammalian choroid plexus. Sci. Am. 261:68-74.

    Google Scholar 

  • Stopa, E. G., Gonzalez, A. M., Chorsky, R., Corona, R. J., Alvarez, J., Bird, E. D., and Baird, A. (1990). Aneurotrophic role for basic fibroblast growth factor in Alzheimer' disease. In Igbal, K., McLachlan, D. R. C., Winblad, B., and Wisniewski, H. M. (eds.), Alzheimer' Disease: Basic Mechanism, Diagnosis and Therapeutic Strategies, John Wiley and Sons, New York, Chap. 37.

    Google Scholar 

  • Takami, K., Iwane, M., Kiyota, Y., Miyamoto, M., Tsukuda, R., and Shiosaka, S. (1992). Increase of basic fibroblast growth factor immunoreactivity and its mRNA level in rat brain following transient forebrain ischemia Exp. Brain Res. 90:1-10.

    Google Scholar 

  • Valentino, K. L., Pham, H., Ocrant, I., and Rosenfeld, R. G. (1988). Distribution of insulin-like growth factor II receptor immunoreactivity in rat tissues. Endocrinology 122:2753-2763.

    Google Scholar 

  • Vega, J. A., Del Valle, M. E., Calzada, B., Bengoechea, M. E., and Perez-Casas, A. (1992). Expression of nerve growth factor receptor immunoreactivity in the rat choroid plexus. Cell. Mol Biol. 38:145-149.

    Google Scholar 

  • Wanaka, A., Johnson, E. M., Jr., and Milbrandt, J. (1990). Localization of FGF receptor mRNA in the adult rat central nervous system by in situ hybridization. Neuron 5:267-281.

    Google Scholar 

  • Yanaka, A., Muto, H., Fukutomi, H., Ito, S., and Silen, W. (1996). Role of transforming growth factor-β in the restitution of injured guinea pig gastric mucosa in vitro. Am. J. Physiol. 271:G75-G85.

    Google Scholar 

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  1. Michael J. Primiano

    Present address: Central Research, Pfizer Pharmaceuticals, Groton, Connecticut, 06340

Authors and Affiliations

  1. Department of Clinical Neurosciences, Brown University/Rhode Island Hospital, Providence, Rhode Island, 02903

    Conrad E. Johanson, Donald E. Palm, Michael J. Primiano & Percy Chan

  2. College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, P.O. Box 367, Tallahassee, Florida, 32307

    Donald E. Palm

  3. Department of Pathology, Brown University/Rhode Island Hospital, Providence, Rhode Island, 02903

    Paul N. McMillan & Edward G. Stopa

  4. Department of Neurosurgery, QE II Medical Centre, Perth, Nedlands, Western Australia, 6009

    Neville W. Knuckey

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Johanson, C.E., Palm, D.E., Primiano, M.J. et al. Choroid Plexus Recovery After Transient Forebrain Ischemia: Role of Growth Factors and Other Repair Mechanisms. Cell Mol Neurobiol 20, 197–216 (2000). https://doi.org/10.1023/A:1007097622590

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