Journal of Neurocytology

, Volume 29, Issue 5–6, pp 401–410 | Cite as

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

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


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.


Animal Model Estrogen Clinical Study Estrogen Receptor Estradiol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 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.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.PubMedGoogle Scholar
  4. 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
  5. BISHOP, J. & SIMPKINS, J. W. (1995) Estradiol enhances brain glucose uptake in ovariectomized rats. Brain Research Bulletin 36, 315–320.PubMedGoogle Scholar
  6. BREDESEN, D. E. (1995) Neural apoptosis. Annals of Neurology 38, 837–851.PubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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
  21. 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.PubMedGoogle Scholar
  22. 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
  23. HENDERSON, V. W., WATT, L. & BUCKWALTER, J. G. (1996) Cognitive skills associated with estrogen replacement inwomenwith AlzheimerÕsdisease. Psychoneuroendocrinology 21, 421–430.CrossRefPubMedGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. KAMPEN, D. L. & SHERWIN, B. B. (1998) Estrogen use and verbal memory in healthy postmenopausal women. Obstetrics and Gynecology 83, 979–983.Google Scholar
  28. 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
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. LONGA, E. Z., WEINSTEIN, P. R., CARLSON, S. & CUMMINS, R. (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. MERRY, D. E. & KORSMEYER, S. J. (1997) Bcl-2 gene family in the nervous system. Annual Review of Neuroscience 20, 245–267.PubMedGoogle Scholar
  41. 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
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. PAGANINI-HILL, A. (1995) Estrogen replacement therapy and stroke. Progress in Cardiovascular Diseases 38, 223–242.PubMedGoogle Scholar
  47. PAGANINI-HILL, A. & HENDERSON, V. W. (1994) Estrogen deficiency and risk of AlzheimerÕsdisease in women. American Journal of Epidemiology 140, 256–261.PubMedGoogle Scholar
  48. PAGANINI-HILL, A. & HENDERSON, V. W. (1996) Estrogen replacement therapy and risk of Alzheimer disease. Archives of Internal Medicine 156, 2213–2217.PubMedGoogle Scholar
  49. PALKOVITS, M. (1978) Topography of chemically identified neurons in the central nervous system: A review. Acta Morphologica Academiae Hungarica 26, 211–290.Google Scholar
  50. 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.PubMedGoogle Scholar
  51. 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
  52. 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.PubMedGoogle Scholar
  53. 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
  54. 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
  55. 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.PubMedGoogle Scholar
  56. SHERWIN, B. B. (1988) Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 13, 345–357.PubMedGoogle Scholar
  57. SHERWIN, B. B. (1994) Estrogenic effects on memory in women. Annals of the New York Academy of Sciences 743, 213–231.PubMedGoogle Scholar
  58. SHERWIN, B. B. (1996) Hormones, mood, and cognitive functioning in postmenopausal women. Obstetrics and Gynecology 87, 20S-26S.PubMedGoogle Scholar
  59. SHERWIN, B. B. (1997) Estrogen effects on cognition in menopausal women. Neurology 48, S21-S26Google Scholar
  60. 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
  61. 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.PubMedGoogle Scholar
  62. SIESJO, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. Journal of Neurosurgery 77, 169–184.PubMedGoogle Scholar
  63. 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.PubMedGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. SUGIOKA, K., SHIMOSEGAWA, Y. & NAKANO, M. (1997) Estradiol as natural antioxidants of membrane phospholipid peroxidation. FEBS Letters 210, 37–39.Google Scholar
  68. 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
  69. 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.PubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 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.PubMedGoogle Scholar
  73. TORAN-ALLERAND, C. D. (1991) Organotypic culture of the developing cerebral cortex and hypothalamus relevance to sexual differentiation. Psychoneuroendocrinology 16, 7–24.PubMedGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Phyllis M. Wise
    • 1
  • Dena B. Dubal
    • 1
  • Melinda E. Wilson
    • 1
  • Shane W. Rau
    • 1
  1. 1.Department of Physiology, College of MedicineUniversity of KentuckyLexingtonUSA

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