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Estradiol is a neuroprotective factor in in vivo and in vitro models of brain injury

  • Published:
Journal of Neurocytology

Abstract

Many clinical studies suggest that estrogen enhances memory and cognition and protects against neurodegenerative diseases and injury associated with stroke or stress. These results are strongly supported by experiments performed in animal models using both in vivo and in vitro methods. We present here data from our lab that establishes that physiological levels of estradiol exert profound protective actions against ischemic injury. Further we will present evidence that these effects may be mediated through estrogen receptors that may influence the bcl-2 family of genes.

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References

  • ALKAYED, N. J., HARUKUNI, I., KIMES, A. S., LONDON, E. D., TRAYSTMAN, R. J. & HURN, P. D. (1998) Gender-linked brain injury in experimental stroke. Stroke 29, 159–166.

    PubMed  Google Scholar 

  • AZCOITIA, I., SIERRA, A. & GARCIA-SEGURA, L. M. (1999) Localization of estrogen receptor beta immunoreactivity in astrocytes of the adult rat brain. Glia 26, 260–267.

    PubMed  Google Scholar 

  • BEAL, M. F., BROUILLET, E., JENKINS, B. J., FERRANTE, R. J., KOWALL, N. W., MILLER, J. M., SRIVASTAVA, R., ROSEN, B. R. & HYMAN, B. T. (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 1-nitroproprionic acid. Journal of Neuroscience 13, 4181–4192.

    PubMed  Google Scholar 

  • BEHL, C., WIDMANN, M., TRAPP, T. & HOLSBOER, F. (1998) 17-? Estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochemical and Biophysical Research Communications 216, 473–482.

    Google Scholar 

  • BISHOP, J. & SIMPKINS, J. W. (1995) Estradiol enhances brain glucose uptake in ovariectomized rats. Brain Research Bulletin 36, 315–320.

    PubMed  Google Scholar 

  • BREDESEN, D. E. (1995) Neural apoptosis. Annals of Neurology 38, 837–851.

    PubMed  Google Scholar 

  • BROOKE, S., CHAN, R., HOWARD, S. & SAPOLSKY, R. (1997) Endocrine modulation of the neurotoxicity of gp120: Implications for AIDS-related dementia complex.Proceedings of the National Academy of Sciences of the USA 94, 9457–9462.

    PubMed  Google Scholar 

  • BROWN, T. J., MACLUSKY, N. J., TORAN-ALLERAND, C. D., ZIELINSKI, J. E. & HOCHBERG, R. B. (1989) Characterization of 11beta-methoxy-16alpha-[125I]iodoestradiol binding: Neuronal localization of estrogenbinding sites in the developing rat brain. Endocrinology 124, 2074–2088.

    PubMed  Google Scholar 

  • DEPAOLO, L. V., SHANDER, D., WISE, P. M., BARRACLOUGH, C. A. & CHANNING, C. P. (1979) Identification of inhibin-like activity in ovarian venous plasma of rats during the estrous cycle. Endocrinology 105, 647–654.

    PubMed  Google Scholar 

  • DUBAL, D. B., KASHON, M. L., PETTIGREW, L. C., REN, J. M., FINKLESTEIN, S. P., RAU, S. W. & WISE, P. M. (1998) Estradiol protects against ischemic injury. Journal of Cerebral Blood Flow and Metabolism 18, 1253–1258.

    PubMed  Google Scholar 

  • FILLIT, H. (1994) Estrogens in the pathogenesis and treatment of AlzheimerÕs disease in postmenopausal women. Annals of the New York Academy of Sciences 743, 233–239.

    PubMed  Google Scholar 

  • GALLYAS, F., ZOLTAY, G. & BALAS, I. (1992) An immediate light microscopic response of neuronal somata, dendrites and axons to contusing concussive head injury in the rat. Acta Neuropathologica 83, 394–401.

    PubMed  Google Scholar 

  • GARCIA-ESTRADA, J., DELRIO, J. A., LUQUIN, S., SORIANO, E. & GARCIA-SEGURA, L. M. (1993) Gonadal hormones down-regulate reactive gliosis and astrocyte proliferation after a penetrating brain injury. Brain Research 628, 271–278.

    Google Scholar 

  • GARCIA-SEGURA, L. M., CARDONA-GOMEZ, P., NAFTOLIN, F. & CHOWEN, J. A. (1998) Estradiol upregulates Bcl-2 expression in adult brain neurons. NeuroReport 9, 593–597.

    PubMed  Google Scholar 

  • GARCIA-SEGURA, L. M., NAFTOLIN, F., HUTCHINSON, J. B., AZCOITIA, I. & CHOWEN, J. A. (1999) Role of astroglia in estrogen regulation of synaptic plasticity and brain repair. Journal of Neurobiology 40, 574–584.

    PubMed  Google Scholar 

  • GOODMAN, Y., BRUCE, A. J., CHENG, B. & MATTSON, M. P. (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid B-peptide toxicity in hippocampal neurons. Journal of Neurochemistry 66, 1836–1844.

    PubMed  Google Scholar 

  • GREEN, P. S., GRIDLEY, K. E. & SIMPKINS, J. W. (1998) Nuclear estrogen receptor-independent neuroprotection by estratrienes: A novel interaction with glutathione. Neuroscience 84, 7–10.

    PubMed  Google Scholar 

  • GREEN, S. G., GRIDLEY, K. E. & SIMPKINS, J. W. (1996) Estradiol protects against ?-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neuroscience Letters 218, 165–168.

    PubMed  Google Scholar 

  • GRIDLEY, K. E., GREEN, P. S. & SIMPKINS, J. W. (1997) Low concentrations of estradiol reduce ?-amyloid (25–35)-induced toxicity, lipid peroxidation and glucose utilization inhumanSK-N-SH neuroblastoma cells. Brain Research 778, 158–165.

    PubMed  Google Scholar 

  • HALL, E. D. & BRAUGHLER, J. M. (1993) Free radicals in CNS injury. In Molecular and Cellular Approaches to the Treatment of Neurological Disease (edited by WAXMAN, S. G., pp. 81–105. New York: Raven Press Ltd.

    Google Scholar 

  • HALL, E. D., PAZARA, K. E. & LINSEMAN, K. L. (1991) Sex differences in postischemic neuronal necrosis in gerbils. Journal of Cerebral Blood Flow and Metabolism 11, 292–298.

    PubMed  Google Scholar 

  • HENDERSON, V. W. & PAGANINI-HILL, A. (1997) Estrogen and AlzheimerÕs Disease. Journal of the Society of Obstetricians and Gynecologists of Canada 19, 21–28.

    Google Scholar 

  • HENDERSON, V. W., WATT, L. & BUCKWALTER, J. G. (1996) Cognitive skills associated with estrogen replacement inwomenwith AlzheimerÕsdisease. Psychoneuroendocrinology 21, 421–430.

    Article  PubMed  Google Scholar 

  • HUANG, Y., RAY, S., REED, J. C., IBRADO, A. M., TANG, C., NAWABI, A. & BHALLA, K. (1997) Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. Breast Cancer Research and Treatment 42, 73–81.

    PubMed  Google Scholar 

  • HURN, P. D., LITTLETON-KEARNEY, M. T., KIRSCH, J. R., DHARMARAJAN, A. M. & TRAYSTMAN, R. J. (1995) Postischemic cerebral blood flow recovery in the female: Effect of 17B-estradiol. Journal of Cerebral Blood Flow and Metabolism 15, 666–672.

    PubMed  Google Scholar 

  • IAFRATI, M. D., KARAS, R. H., ARONOVITZ, M., KIM, S., SULLIVAN, T. R., LUBAHN, D. B., OÕDONNELL, T. F., JR., KORACH, K. S. & MENDELSOHN, M. E. (1997) Estrogen inhibits the vascular injury response in estrogen receptor ?-deficient mice. Nature Medicine 3, 545–548.

    Article  PubMed  Google Scholar 

  • KAMPEN, D. L. & SHERWIN, B. B. (1998) Estrogen use and verbal memory in healthy postmenopausal women. Obstetrics and Gynecology 83, 979–983.

    Google Scholar 

  • KANDOUZ, M., SIROMACHKOVA, M., JACOB, D., MARQUET, B. C., THERWATH, A. & GOMPEL, A. (1996) Antagonism between estradiol and progestin on bcl-2 expression in breast-cancer cells. International Journal of Cancer 68, 120–125.

    Google Scholar 

  • KAWAS, C., RESNICK, S., MORRISON, A., BROOKMEYER, R., CORRADA, M., ZONDERMAN, A., BACAL, C., LINGLE, D. & METTER, E. (1997) A prospective study of estrogen replacement therapy and the risk of developing AlzheimerÕs disease: The Baltimore Longitudinal Study of Aging. Neurology 48, 1517–1521.

    PubMed  Google Scholar 

  • KITAGAWA, K., MATSUMOTO, M., TSUJIMOTO, Y., OHTSUKI, T., KUWABARA, K., MATSUSHITA, K., YANG, G., TANABE, H., MARTINOU, J.-C., HORI, M. & YANAGIHARA, T. (1998) Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice. Stroke 29, 2616–2621.

    PubMed  Google Scholar 

  • KOMESAROFF, P. A., ESLER, M. D. & KRISHNANKUTTY, S. (1999) Estrogen supplementation attenuates glucocorticoid and catesholamine responses to mental stress in perimenopausal women. Journal of Clinical Endocrinology and Metabolism 84, 606–610.

    PubMed  Google Scholar 

  • KRAJEWSKI, S., MAI, J. K., KRAJEWSKA, M., SIKORSKA, M., MOSSAKOWSKI, M. J. & REED, J. C. (1995) Upregulation of bax protein levels in neurons following cerebral ischemia. Journal of Neuroscience 15, 6364–6375.

    PubMed  Google Scholar 

  • KUIPER, G. G. J. M., ENMARK, E., PELTO-HUIKKO, M., NILSSON, S. & GUSTAFSSON, J.-A. (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences USA 93, 5925–5930.

    Google Scholar 

  • KUMAR, M., LIU, G.-J., FLOYD, R. A. & GRAMMAS, P. (1996) Anoxic injury of endothelial cells increases production of nitric oxide and hydroxyl radicals. Biochemical and Biophysical Research Communications 219, 497–501.

    PubMed  Google Scholar 

  • LANGUB, M. C., JR. & WATSON, R. E., JR. (1992) Estrogen receptor-immunoreactive glia, endothelia, and ependyma in guinea pig preoptic area and median eminence: Electron microscopy. Endocrinology 130, 364–372.

    PubMed  Google Scholar 

  • LINDNER, V., KIM, S. K., KARAS, R. H., KUIPER, G. G. J. M., GUSTAFSSON, J.-A. & MENDELSOHN, M. E. (1998) Increased expression of estrogen receptor-? mRNA in male blood vessels after vascular injury. Circulation Research 83, 224–229.

    PubMed  Google Scholar 

  • LONGA, E. Z., WEINSTEIN, P. R., CARLSON, S. & CUMMINS, R. (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91.

    PubMed  Google Scholar 

  • MACMANUS, J. P. & LINNIK, M. D. (1997) Gene expression induced by cerebral ischemia: An apoptotic perspective. Journal of Cerebral Blood Flow and Metabolism 17, 815–832.

    PubMed  Google Scholar 

  • MARTINOU, J.-C., DUBOIS-DAUPHIN, M., STAPLE, J. K., RODRIGUEZ, I., FRANKOWSKI, H., MISSOTTEN, M., ALBERTINI, P., TALABOT, D., CATSICAS, S., PIETRA, C. & HUARTE, J. (1994) Overexpression of bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13, 1017–1030.

    PubMed  Google Scholar 

  • MERRY, D. E. & KORSMEYER, S. J. (1997) Bcl-2 gene family in the nervous system. Annual Review of Neuroscience 20, 245–267.

    PubMed  Google Scholar 

  • MIRANDA, R. C., SOHRABJI, F. & TORAN-ALLERAND, C. D. (1993) Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions. Proceedings of the National Academy of Science,USA 90, 6439–6443.

    Google Scholar 

  • MIRANDA, R. C., SOHRABJI, F. & TORAN-ALLERAND, D. (1994) Interactions of estrogen with the neurotrophins and their receptors during neural development. Hormones and Behavior 28, 367–375.

    PubMed  Google Scholar 

  • MYERS, K. M., FISKUM, G., LIU, Y., SIMMENS, S. J., BREDESEN, D. E. & MURPHY, A. N. (1995) Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. Journal of Neurochemistry 65, 2432–2440.

    PubMed  Google Scholar 

  • NAKAO, N., KOKAIA, Z., ODIN, P. & LINDVALL, O. (1995) Protective effects ofBDNFand NT-3 but notPDGF against hypoglycemic injury to cultured striatal neurons. Experimental Neurology 131, 1–10.

    PubMed  Google Scholar 

  • NAMURA, S., ZHU, J., FINK, K., ENDRES, M., SRINIVASAN, A., TOMASELLI, K. J., YUAN, J. & MOSKOWITZ, M. A. (1998) Activation and cleavage of caspase-3 in apoptosis induced by cerebral ischemia. Journal of Neuroscience 18, 3659–3668.

    PubMed  Google Scholar 

  • PAGANINI-HILL, A. (1995) Estrogen replacement therapy and stroke. Progress in Cardiovascular Diseases 38, 223–242.

    PubMed  Google Scholar 

  • PAGANINI-HILL, A. & HENDERSON, V. W. (1994) Estrogen deficiency and risk of AlzheimerÕsdisease in women. American Journal of Epidemiology 140, 256–261.

    PubMed  Google Scholar 

  • PAGANINI-HILL, A. & HENDERSON, V. W. (1996) Estrogen replacement therapy and risk of Alzheimer disease. Archives of Internal Medicine 156, 2213–2217.

    PubMed  Google Scholar 

  • PALKOVITS, M. (1978) Topography of chemically identified neurons in the central nervous system: A review. Acta Morphologica Academiae Hungarica 26, 211–290.

    Google Scholar 

  • PANG, Z. & GEDDES, J. W. (1997) Mechanisms of cell death induced by the mitochondrial toxin 3-nitroproionic acid: Acute excitotoxic necrosis and delayed apoptosis. Journal of Neuroscience 17, 3064–3073.

    PubMed  Google Scholar 

  • PELLIGRINO, D. A., BAUGHMAN, V. L. & KOENIG, H. M. (1996) Nitric oxide and the brain. In Topics in Neuroanesthesia (edited by JAFFE, R. A. & GIFFARD, R. G.) pp. 113–132. Boston: Little, Brown and Company.

    Google Scholar 

  • REGAN, R. F. & GUO, Y. (1997) Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. Brain Research 764, 133–140.

    PubMed  Google Scholar 

  • SATO, S., GOBBEL, G. T., HONKANIEMI, J., LI, Y., KONDO, T., MURAKAMI, K., SATO, M., COPIN, J.-C., SHARP, F. R. & CHAN, P. H. (1998) Decreased expression of bcl-2 ad bcl-x mRNA coincides with apoptosis following intracerebral administration of 3-nitropropionic acid. Brain Research XXX, 56–64.

    Google Scholar 

  • SCHMIDT, R., FAZEKAS, F., REINHART, B., KAPELLER, P., FAZEKAS, G., OFFENBACHER, H., EBER, B., SCHUMACHER, M. & FREIDL, W. (1996) Estrogen replacement therapy in older women: A neuropsychological and brain MRI study. Journal of the American Geriatrics Society 44, 1307–1313.

    Google Scholar 

  • SCHWOB, J. E., FULLER, T., PRICE, J. L. & OLNEY, J. W. (1980) Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: A histological stydy. Neuroscience 5, 991–1014.

    PubMed  Google Scholar 

  • SHERWIN, B. B. (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13, 345–357.

    PubMed  Google Scholar 

  • SHERWIN, B. B. (1994) Estrogenic effects on memory in women. Annals of the New York Academy of Sciences 743, 213–231.

    PubMed  Google Scholar 

  • SHERWIN, B. B. (1996) Hormones, mood, and cognitive functioning in postmenopausal women. Obstetrics and Gynecology 87, 20S-26S.

    PubMed  Google Scholar 

  • SHERWIN, B. B. (1997) Estrogen effects on cognition in menopausal women. Neurology 48, S21-S26

    Google Scholar 

  • SHERWIN, B. B. & CARLSON, L. E. (1997) Estrogen and Memory in Women. Journal of the Society of Obstetricians and Gynecologists of Canada 19, 7–13.

    Google Scholar 

  • SHUGHRUE, P. J., LANE, M. V. & MERCHENTHALER, I. (1997) Comparative distribution of estrogen receptor-? and-? mRNA in the rat central nervous system. Journal of Comparative Neurology 388, 507–525.

    PubMed  Google Scholar 

  • SIESJO, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. Journal of Neurosurgery 77, 169–184.

    PubMed  Google Scholar 

  • SIMPKINS, J. W., RAJAKUMAR, G., ZHANG, Y.-Q., SIMPKINS, C. E., GREENWALD, D., YU, C. J., BODOR, N. & DAY, A. L. (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. Journal of Neurosurgery 87, 724–730.

    PubMed  Google Scholar 

  • SINGER, C. A., ROGERS, K. L., STRICKLAND, T. M. & DORSA, D. M. (1996) Estrogen protects primary cortical neurons from glutamate toxicity. Neuroscience Letters 212, 13–16.

    PubMed  Google Scholar 

  • SMITH, M. S., FREEMAN, M. E. & NEILL, J. D. (1975) The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: Prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96, 219–226.

    PubMed  Google Scholar 

  • STONE, D. J., SONG, Y., ANDERSON, C. P., KROHN, K. K., FINCH, C. E. & ROZOVSKY, I. (1998) Bidirectional transcriptional regulation of glial fibrillary acidic protein by estradiol in vivo and in vitro. Endocrinology 139, 3202–3209.

    PubMed  Google Scholar 

  • SUGIOKA, K., SHIMOSEGAWA, Y. & NAKANO, M. (1997) Estradiol as natural antioxidants of membrane phospholipid peroxidation. FEBS Letters 210, 37–39.

    Google Scholar 

  • TANG, M.-X., JACOBS, D., STERN, Y., MARDER, K., SCHOFIELD, P., GURLAND, B., ANDREWS, H. & MAYEUX, R. (1996) Effect of oestrogen during menopause on risk and age at onset of AlzheimerÕs disease. The Lancet 348, 429–432.

    Google Scholar 

  • TEIXEIRA, C., REED, J. C. & PRATT, M. A. C. (1995) Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Research 55, 3902–3907.

    PubMed  Google Scholar 

  • TOMBAUGH, G. C., YANG, S. H., SWANSON, R. A. & SAPOLSKY, R. M. (1992) Glucocorticoids exacerbate hypoxic and hypoglycemic hippocampal injury in vitro: Biochemical correlates and a role for astrocytes. Journal of Neurochemistry 59, 137–146.

    PubMed  Google Scholar 

  • TORAN-ALLERAND, C. D. (1976) Sex steroids and the development of the newborn mouse hypothalamus and preoptic area in vitro: Implications for sexual differentiation. Brain Research 106, 407–412.

    PubMed  Google Scholar 

  • TORAN-ALLERAND, C. D. (1984) On the genesis of sexual 410 WISE, DUBAL, WILSON and RAU differentiation of the central nervous system: Morphogenetic consequences of steroidal exposure and possible role of a-fetoprotein. Progress in Brain Research 61, 63–98.

    PubMed  Google Scholar 

  • TORAN-ALLERAND, C. D. (1991) Organotypic culture of the developing cerebral cortex and hypothalamus relevance to sexual differentiation. Psychoneuroendocrinology 16, 7–24.

    PubMed  Google Scholar 

  • TORAN-ALLERAND, C. D. (1996) Mechanisms of estrogen action during neural development: Mediation by interactions with the neurotrophins and their receptors. Journal of Steroid Biochemistry and Molecular Biology 56, 169–178.

    PubMed  Google Scholar 

  • TORAN-ALLERAND, C. D., MIRANDA, R. C., HOCHBERG, R. B. & MACLUSKY, N. J. (1992) Cellular variations in estrogen receptor mRNA translation in the developing brain: Evidence from combined [125I]estrogen autoradiography and non-isotopic in situ hybridization histochemistry. Brain Research 576, 25–41.

    PubMed  Google Scholar 

  • WEAVER, C. E., JR., PARK-CHUNG, M., GIBBS, T. T. & FARB, D. H. (1997) 17-?-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors. Brain Research 761, 338–341.

    PubMed  Google Scholar 

  • WISE, P. M., CAMP-GROSSMAN, P. & BARRACLOUGH, C. A. (1981) Effects of estradiol and progesterone on plasma gonadotropins, prolactin, and LHRH in specific brain areas of ovariectomized rats. Biology of Reproduction 24, 820–830.

    PubMed  Google Scholar 

  • YANG, L., MATTHEWS, R. T., SCHULZ, J. B., KLOCKGETHER, T., LIAO, A. W., MARTINOU, J.-C., PENNEY, J. B., JR., HYMAN, B. T. & BEAL, M. F. (1998) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2. Journal of Neuroscience 18, 8145–8152.

    PubMed  Google Scholar 

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  1. Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, 40536, USA

    Phyllis M. Wise, Dena B. Dubal, Melinda E. Wilson & Shane W. Rau

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  1. Phyllis M. Wise
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  2. Dena B. Dubal
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  3. Melinda E. Wilson
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  4. Shane W. Rau
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Wise, P.M., Dubal, D.B., Wilson, M.E. et al. Estradiol is a neuroprotective factor in in vivo and in vitro models of brain injury. J Neurocytol 29, 401–410 (2000). https://doi.org/10.1023/A:1007169408561

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