Neurochemical Research

, Volume 25, Issue 9–10, pp 1219–1231 | Cite as

Allostasis, Allostatic Load, and the Aging Nervous System: Role of Excitatory Amino Acids and Excitotoxicity

  • Bruce S. McEwen


The adaptive responses of the body to challenges, often known as “stressors”, consists of active responses that maintain homeostasis. This process of adaptation is known as “allostasis”, meaning “achieving stability through change”. Many systems of the body show allostasis, including the autonomic nervous system and hypothalamo-pituitary-adrenal (HPA) axis and they help to re-establish or maintain homeostasis through adaptation. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body that has been termed “allostatic load”. Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Circulating stress hormones play a key role, and, in the hippocampus, excitatory amino acids and NMDA receptors are important mediators of neuronal atrophy. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Yet, at the same time, excitatory amino acids and NMDA receptors mediate important types of plasticity in the hippocampus. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. This review discusses the current status of work on underlying mechanisms for these effects.

Allostasis allostatic load aging brain excitatory amino acid excitotoxicity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sterling, P. and Eyer, J. 1988. Allostasis: A New Paradigm to Explain Arousal Pathology. In Fisher, S., and J. Reason, eds. Handbook of Life Stress, Cognition and Health. New York, John Wiley & Sons., 629-649.Google Scholar
  2. 2.
    McEwen, B. S. and Stellar, E. 1993. Stress and the Individual: Mechanisms leading to disease. Archives of Internal Medicine 153:2093-2101.Google Scholar
  3. 3.
    McEwen, B. S. 1998. Protective and Damaging Effects of Stress Mediators. New England J. Med. 338:171-179.Google Scholar
  4. 4.
    Seeman, T. E., Singer, B. H., Rowe, J. W., Horwitz, R. I., and McEwen, B. S. 1997. Price of adaptation-allostatic load and its health consequences: MacArthur studies of successful aging. Arch. Intern. Med. 157:2259-2268.Google Scholar
  5. 5.
    Landfield, P., Waymire, J., and Lynch, G. 1978. Hippocampal aging and adrenocorticoids: quantitative correlation. Science 202:1098-1101.Google Scholar
  6. 6.
    Landfield, P. 1987. Modulation of brain aging correlates by long-term alterations of adrenal steroids and neurally-active peptides. Prob. Brain Res. 72:279-300.Google Scholar
  7. 7.
    Sapolsky, R. 1992. Stress, the Aging Brain and the Mechanisms of Neuron Death. Cambridge MIT Press 1:423.Google Scholar
  8. 8.
    Lupien, S., Lecours, A. R., Lussier, I., Schwartz, G., Nair, N. P. V., and Meaney, M. J. 1994. Basal cortisol levels and cognitive deficits in human aging. J. Neurosci. 14:2893-2903.Google Scholar
  9. 9.
    Seeman, T. E., McEwen, B. S., Singer, B. H., Albert, M. S., and Rowe, J. W. 1997. Increase in Urinary Cortisol Excretion and Memory Declines: MacArthur Studies of Successful Aging. J. Clin. Endocr. Metab. 82:2458-2465.Google Scholar
  10. 10.
    Lupien, S. J., DeLeon, M. J., De Santi, S., Convit, A., Tarshish, C., Nair, N. P. V., Thakur, M., McEwen, B. S., Hauger, R. L., and Meaney, M. J. 1998. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neuroscience 1:69-73.Google Scholar
  11. 11.
    Eichenbaum, H. 1997. How does the brain organize memories? Science 277:330-332.Google Scholar
  12. 12.
    DeKloet, E. R., Vreugdenhil, E., Oitzl, M. S., and Joels, M. 1998. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19:269-301.Google Scholar
  13. 13.
    Sapolsky, R., Krey, L., and McEwen, B. S. 1986. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7:284-301.Google Scholar
  14. 14.
    McEwen, B. S., Albeck, D., Cameron, H., Chao, H. M., Gould, E., Hastings, N., Kuroda, Y., Luine, V., Magarinos, A. M., McKittrick, C. R., Orchinik, M., Pavlides, C., Vaher, P., Watanabe, Y., and Weiland, N. 1995. Stress and the Brain: A Paradoxical Role for Adrenal Steroids. In Litwack, G. D., ed. Vitamins And Hormones. Academic Press, Inc., 371-402.Google Scholar
  15. 15.
    Cameron, H. A. and Gould, E. 1996. The Control of Neuronal Birth and Survival. In Shaw, C. A., ed. Receptor Dynamics in Neural Development. New York, CRC Press, 141-157.Google Scholar
  16. 16.
    McEwen, B. S. 1999. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22:105-122.Google Scholar
  17. 17.
    McEwen, B. S. and Alves, S. H. 1999. Estrogen Actions in the Central Nervous System. Endocr. Rev. 20:279-307.Google Scholar
  18. 18.
    Landfield, P. W. and Eldridge, J. C. 1994. Evolving aspects of the glucocorticoid hypothesis of brain aging: Hormonal modulation of neuronal calcium homeostasis. Neurobiol. Aging 15:579-588.Google Scholar
  19. 19.
    Porter, N. M., Thibault, O., Thibault, V., Chen, K.-C., and Land-field, P. W. 1997. Calcium channel density and hippocampal cell death with age in long-term culture. J. Neurosci. 17:5629-5639.Google Scholar
  20. 20.
    Norris, C. M., Halpain, S., and Foster, T. C. 1998. Reversal of age-related alterations in synaptic plasticity by blockade of Ltype Ca2+channels. J. Neurosci 18:3171-3179.Google Scholar
  21. 21.
    Maren, S. 1995. Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory. Neurobiol. Learning & Mem. 63:1-18.Google Scholar
  22. 22.
    Joels, M. 1997. Steroid hormones and excitability in the mammalian brain. Frontiers in Neuroendocrinol. 18:2-48.Google Scholar
  23. 23.
    Kerr, S., Campbell, L., Applegate, M., Brodish, A., and Land-field, P. 1991. Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J. Neurosci. 11:1316-1324.Google Scholar
  24. 24.
    McCord, J. 1985. Oxygen-derived free radicals in postischemic tissue injury. New Engl. J. Med. 312:159-163.Google Scholar
  25. 25.
    Liu, J., Fischer, A., Amiri, N., Timiras, P. S., and Ames, B. N. 1998. Stress-induced oxidative damage in the brain: stress hormones enhance, but an antistress hormone (DHEA), inhibits, oxidative damage and beta-amyloid production in cell culture. Oxygen Society Meeting Poster.Google Scholar
  26. 26.
    Rasmussen, T., Schliemann, T., Sorensen, J. C., Zimmer, J., and West, M. J. 1996. Memory Impaired Aged Rats: No loss of Principal Hippocampal and Subicular Neurons. Neurobiol. Aging 14:143-147.Google Scholar
  27. 27.
    Rapp, P. R. and Gallagher, M. 1996. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc. Natl. Acad. Sci. USA 93:9926-9930.Google Scholar
  28. 28.
    McEwen, B. S. 1999. Stress and the Aging Hippocampus. Frontiers in Neuroendocrinol. 20:49-70.Google Scholar
  29. 29.
    Sugaya, K., Chouinard, M., Greene, R., Robbins, M., Personett, D., Kent, C., Gallagher, M., and McKinney, M. 1996. Molecular Indices of Neuronal and Glial Plasticity in the Hippocampal Formation in a Rodent Model of Age-Induced Spatial Learning Impairment. J. Neurosci. 16:3427-3443.Google Scholar
  30. 30.
    Chan, P. H. 1996. Role of oxidants in ischemic brain damage. Stroke 27:1124-1129.Google Scholar
  31. 31.
    Lowy, M. T., Gault, L., and Yamamoto, B. K. 1993. Adrenalectomy Attenuates Stress-Induced Elevations in Extracellular Glutamate Concentrations in the Hippocampus. J. Neurochem. 61:1957-1960.Google Scholar
  32. 32.
    Moghaddam, B., Boliano, M. L., Stein-Behrens, B., and Sapolsky, R. 1994. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res. 655:251-254.Google Scholar
  33. 33.
    Schaasfoort, E., DeBrin, L., and Korf, J. 1988. Mild stress stimulates rat hippocampal glucose utilization transiently via NMDA receptors as assessed by lactography. Brain Res. 575:58-63.Google Scholar
  34. 34.
    De Bruin, L. A., Schasfoort, M. C., Stefens, A. B., and Korf, J. 1994. Effects of stress and exercise on rat hippocampus and striatum extracellular lactate. Am. J. Physiol. 259:R773-R779.Google Scholar
  35. 35.
    Lowy, M. T., Wittenberg, L., and Yamamoto, B. K. 1995. Effect of Acute Stress on Hippocampal Glutamate Levels and Spectrin Proteolysis in Young and Aged Rats. J. Neurochem. 65:268-274.Google Scholar
  36. 36.
    Reagan, L. P., and McEwen, B. S. 1997. Controversies surrounding glucocorticoid-mediated cell death in the hippocampus. J. Chem. Neuroanat. 13:149-167.Google Scholar
  37. 37.
    Keller, J. N. and Mattson, M. P. 1998. Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. Reviews in Neurosci. 9:105-116.Google Scholar
  38. 38.
    Maren, S. 1999. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. TINS 22:561-567.Google Scholar
  39. 39.
    Bliss, T. V. P. and Collingridge, G. L. 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31-39.Google Scholar
  40. 40.
    Choi, D. 1988. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. TINS 11: 465-469.Google Scholar
  41. 41.
    Weiland, N. G., Orchinik, M., and Tanapat, P. 1997. Chronic corticosterone treatment induces parallel changes in N-methyl-Daspartate receptor subunit messenger RNA levels and antagonist binding sites in the hippocampus. Neuroscience 78:653-662.Google Scholar
  42. 42.
    Bartanusz, V., Aubry, J. M., Pagliusi, S., Jezova, D., Baffi, J., and Kiss, J. Z. 1995. Stress-Induced Changes in Messenger RNA Levels of N-Methyl-D-Aspartate and Ampa Receptor Subunits in Selected Regions of the Rat Hippocampus and Hypothalamus. Neuroscience 66:247-252.Google Scholar
  43. 43.
    Weinstock, M., Poltyrev, T., Schorer-Apelbaum, D., Men, D., and McCarty, R. 1998. Effect of prenatal stress on plasma corticosterone and catecholamines in response to footshock in rats. Physiol. & Behav. 64:439-444.Google Scholar
  44. 44.
    Ader, R. 1968. Effects of early experiences on emotional and physiological reactivity in the rat. J. Comp. Physiol. Psych. 66: 264-268.Google Scholar
  45. 45.
    Hess, J. L., Denenberg, V. H., Zarrow, M. X., and Pfeifer, W. D. 1968. Modification of the corticosterone response curve as a function of handling in infancy. Physiol. & Behav. 4: 109-111.Google Scholar
  46. 46.
    Levine, S., Haltmeyer, G., Kara, G., and Denenberg, V. 1967. Physiological and behavioral effects of infantile stimulation. Physiol. Behav. 2:55-59.Google Scholar
  47. 47.
    Dellu, F., Mayo, W., Vallee, M., LeMoal, M., and Simon, H. 1994. Reactivity to novelty during youth as a predictive factor of cognitive impairment in the elderly: a longitudinal study in rats. Brain Res. 653:51-56.Google Scholar
  48. 48.
    Piazza, P. V., Marinelli, M., Jodogne, C., Deroche, V., Rouge-Pont, F., Maccari, S., Le Moal, M., and Simon, H. 1994. Inhibition of corticosterone synthesis by Metrapone decreases cocaine-induced locomotion and relapse of cocaine self-administration. Brain Res. 658:259-264.Google Scholar
  49. 49.
    Deroche, V., Piazza, P. V., LeMoal, M., and Simon, H. 1993. Individual differences in the psychomotor effects of morphine are predicted by reactivity to novelty and influenced by corticosterone secretion. Brain Res. 623:341-344.Google Scholar
  50. 50.
    Meaney, M., Aitken, D., Berkel, H., Bhatnager, S., and Sapolsky, R. 1988. Effect of neonatal handling of age-related impairments associated with the hippocampus. Science 239:766-768.Google Scholar
  51. 51.
    Catalani, A., Marinelli, M., Scaccianoce, S., Nicolai, R., Muscolo, L. A. A., Porcu, A., Koranyi, L., Piazza, P. V., and Angelucci, L. 1993. Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance. Brain Res. 624:209-215.Google Scholar
  52. 52.
    Meaney, M. J., Tannenbaum, B., Francis, D., Bhatnagar, S., Shanks, N., Viau, V., O'Donnell, D., and Plotsky, P. M. 1994. Early environmental programming hypothalamic-pituitary-adrenal responses to stress. Seminars in Neurosci. 6:247-259.Google Scholar
  53. 53.
    Pavlides, C., Kimura, A., Magarinos, A. M., and McEwen, B. S. 1995. Hippocampal homosynaptic long-term depression/ depotentiation induced by adrenal steroids. Neuroscience 68:379-385.Google Scholar
  54. 54.
    Pavlides, C., Watanabe, Y., Magarinos, A. M., and McEwen, B. S. 1995. Opposing role of adrenal steroid Type I and Type II receptors in hippocampal long-term potentiation. Neuroscience 68:387-394.Google Scholar
  55. 55.
    Pavlides, C., Kimura, A., Magarinos, A. M., and McEwen, B. S. 1994. Type I adrenal steroid receptors prolong hippocampal long-term potentiation. NeuroReport 5:2673-2677.Google Scholar
  56. 56.
    Kerr, D. S., Huggett, A. M., and Abraham, W. C. 1994. Modulation of hippocampal long-term potentiation and long-term depression by corticosteroid receptor activation. Psychobiology 22:123-133.Google Scholar
  57. 57.
    Barnes, C., McNaughton, B., Goddard, G., Douglas, R., and Adamec, R. 1977. Circadian rhythm of synaptic excitability in rat and monkey central nervous system. Science 197:91-92.Google Scholar
  58. 58.
    Dana, R. C. and Martinez, J. L. 1984. Effect of adrenalectomy on the circadian rhythm of LTP. Brain Res. 308:392-395.Google Scholar
  59. 59.
    Diamond, D. M., Bennett, M. C., Fleshner, M., and Rose, G. M. 1992. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2:421-430.Google Scholar
  60. 60.
    Diamond, D. M., Fleshner, M., Ingersoll, N., and Rose, G. M. 1996. Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. Behav. Neurosci. 110:661-672.Google Scholar
  61. 61.
    Roozendaal, B. and McGaugh, J. L. 1997. Glucocorticoid receptor agonist and antagonist administration into the basolateral but not central amygdala modulates memory storage. Neurobiol. Learning & Mem. 67:176-179.Google Scholar
  62. 62.
    Corodimas, K. P., LeDoux, J. E., Gold, P. W., and Schulkin, J. 1994. Corticosterone potentiation of learned fear. Annals of the New York Acad. Sci. 746:392.Google Scholar
  63. 63.
    Diamond, D. M., Fleshner, M., and Rose, G. M. 1994. Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats. Behav. Brain Research 62:1-9.Google Scholar
  64. 64.
    deQuervain, D. J. F., Roozendaal, B., and McGaugh, J. L. 1998. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394:787-790.Google Scholar
  65. 65.
    Galea, L. A. M., Tanapat, P., and Gould, E. 1996. Exposure to predator odor suppresses cell proliferation in the dentate gyrus of adult rats via a cholinergic mechanism. Abstract, Soc. Neurosci. 22:#474.8, p.1196.Google Scholar
  66. 66.
    Ikegaya, Y., Saito, H., and Abe, K. 1997. The basomedial and basolateral amygdaloid nuclei contribute to the induction of long-term potentiation in the dentate gyrus in vivo. Eur. J. Neurosci. 8:1833-1839.Google Scholar
  67. 67.
    LeDoux, J. E. 1995. In search of an emotional system in the brain: leaping from fear to emotion and consciousness. In Gazzaniga, M., ed. The Cognitive Neurosciences. Cambridge, MIT Press, 1049-1061.Google Scholar
  68. 68.
    Woolley, C., Gould, E., Frankfurt, M., and McEwen, B. S. 1990. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci. 10:4035-4039.Google Scholar
  69. 69.
    Popov, V. I. and Bocharova, L. S. 1992. Hibernation-induced structural changes in synaptic contacts between mossy fibres and hippocampal pyramidal neurons. Neuroscience 48:53-62.Google Scholar
  70. 70.
    Popov, V. I., Bocharova, L. S., and Bragin, A. G. 1992. Repeated changes of dendritic morphology in the hippocampus of ground squirrels in the course of hibernation. Neuroscience 48:45-51.Google Scholar
  71. 71.
    McEwen, B. S. and Woolley, C. S. 1994. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp. Geront. 29:431-436.Google Scholar
  72. 72.
    McEwen, B. S., Gould, E., Orchinik, M., Weiland, N. G., and Woolley, C. S. 1995. Oestrogens and the structural and functional plasticity of neurons: implications for memory, aging and neurodegenerative processes. In Goode, J., ed. Ciba Foundation Symposium #191 The Non-reproductive Actions of Sex Steroids. London, CIBA Foundation, 52-73.Google Scholar
  73. 73.
    Cameron, H. A. and Gould, E. 1994. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61:203-209.Google Scholar
  74. 74.
    Woolley, C. and McEwen, B. S. 1994. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor dependent mechanism. J. Neurosci. 14:7680-7687.Google Scholar
  75. 75.
    Magarinos, A. M. and McEwen, B. S. 1995. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69:89-98.Google Scholar
  76. 76.
    Weiland, N. G. 1992. Estradiol Selectively Regulates Agonist Binding Sites on the N-Methyl-D-Aspartate Receptor Complex in the CA1 Region of the Hippocampus. Endocrinology 131: 662-668.Google Scholar
  77. 77.
    Gazzaley, A. H., Benson, D. L., Huntley, G. W., and Morrison, J. H. 1997. Differential subcellular regulation of NMDAR1 protein and mRNA in dendrites of dentate gyrus granule cells after perforant path transection. J. Neurosci. 17:2006-2017.Google Scholar
  78. 78.
    Gould, E. 1999. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21:46S-51S.Google Scholar
  79. 79.
    van Praag, H., Kempermann, G., and Gage, F. H. 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2:266-270Google Scholar
  80. 80.
    Kempermann, G., Kuhn, H. G., and Gage, F. H. 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature 586:493-495.Google Scholar
  81. 81.
    Conrad, C. D., Magarinos, A. M., LeDoux, J. E., and McEwen, B. S. 1999. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113:1-12.Google Scholar
  82. 82.
    Eldridge, J. C., Brodish, A., Kute, T. E., and Landfield, P. W. 1989. Apparent age-related resistance of type II hippocampal corticosteroid receptors to down-regulation during chronic escape training. J. Neurosci. 9:3237-3242.Google Scholar
  83. 83.
    Cameron, H. A. and McKay, D. G. 1999. Restoring production of hippocampal neurons in old age. Nature Neurosci. 2:894-858.Google Scholar
  84. 84.
    Tanapat, P., Hastings, N. B., Reeves, A. J., and Gould, E. 1999. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J. Neurosci. 19:5792-5801.Google Scholar
  85. 85.
    Galea, L. A. M., McEwen, B. S., Tanapat, P., Deak, T., Spencer, R. L., and Dhabhar, F. S. 1997. Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience 81:689-697.Google Scholar
  86. 86.
    Gould, E., Westlind-Danielsson, A., Frankfurt, M., and McEwen, B. S. 1990. Sex differences and thyroid hormone sensitivity of hippocampal pyramidal neurons. J. Neurosci. 10: 996-1003.Google Scholar
  87. 87.
    Williams, C. L. and Meck, W. H. 1991. The organizational effects of gonadal steroids on sexually dimorphic spatial ability. Psychoneuroendocrinology 16:155-176.Google Scholar
  88. 88.
    Juraska, J. M. 1991. Sex differences in "cognitive" regions of the rat brain. Psychoneuroendocrinology 16:105-119.Google Scholar
  89. 89.
    Roof, R. L. 1993. The dentate gyrus is sexually dimorphic in prepubescent rats: testosterone plays a significant role. Brain Res. 610:148-151.Google Scholar
  90. 90.
    Van Cauter, E., Leproult, R., and Kupfer, D. J. 1996. Effects of Gender and Age on the Levels and Circadian Rhythmicity of Plasma Cortisol. J. Clin. Endocrinol. & Metabol. 81:2468-2473.Google Scholar
  91. 91.
    Komesaroff, P. A., Esler, M. D., and Sudhir, K. 1999. Estrogen supplementation attenuates glucocorticoid and catecholamine responses to mental stress in perimenopausal women. J. Clin. Endocrinol. & Metab. 84:606-610Google Scholar
  92. 92.
    Goodman, Y., Bruce, A. J., Cheng, B., and Mattson, M. P. 1996. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem. 66:1836-1844.Google Scholar
  93. 93.
    Hawk, T., Zhang, Y.-Q., Rajakumar, G., Day, A. L., and Simpkins, J. W. 1998. Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats. Brain Res. 796:296-298.Google Scholar
  94. 94.
    Dubal, D. B., Shughrue, P. J., Wilson, M. E., Merchenthaler, I., and Wise, P. M. 1999. Estradiol modulates bcl-2 in cerebral ischemia: A potential role for estrogen receptors. J. Neurosci. 19:6385-6393.Google Scholar
  95. 95.
    Sapolsky, R. and Pulsinelli, W. 1985. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229:1397-1399.Google Scholar
  96. 96.
    Uno, H., Ross, T., Else, J., Suleman, M., and Sapolsky, R. 1989. Hippocampal damage associated with prolonged and fatal stress in primates. J. Neurosci 9:1709-1711.Google Scholar
  97. 97.
    Henderson, V. W. and Paganini-Hill, A. 1994. Oestrogens and Alzheimer's disease. Ann. Prog. Rep. Med. 2:1-21.Google Scholar
  98. 98.
    Tang, M. X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., Andrews, H., and Mayeux, R. 1996. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 348:429-432.Google Scholar
  99. 99.
    Kawas, C., Resnick, S., Morrison, A., Brookmeyer, R., Corrada, M., Zonderman, A., Bacal, C., Lingle, D. D., and Metter, E. 1997. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 48:1517-1521.Google Scholar
  100. 100.
    Green, P. S., Gridley, K. E., and Simpkins, J. W. 1996. Estradiol protects against β-amyloid (25-35)-induced toxicity in SK-NSH human neuroblastoma cells. Neurosci. Lett. 218:165-168.Google Scholar
  101. 101.
    Blaylock, R. L. 1999. Neurodegeneration and aging of the central nervous system: Prevention and treatment by phytochemicals and metabolic nutrients. Integrat. Med. 1:117-133Google Scholar
  102. 102.
    Kuiper, G. G. J. M., Lemmen, J. G., Carlsson, B., Corton, J. C., Safe, S. H., van der Saag, P. T., van der Burg, B., and Gustafsson, J.-A. 1998. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139:4252-4263.Google Scholar
  103. 103.
    Bishop, J. and Simpkins, J. W. 1994. Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro. Mol. & Cell. Neurosci. 5:303-308.Google Scholar
  104. 104.
    Green, P. S., Bishop, J., and Simpkins, J. W. 1997. 17α-Estradiol exerts neuroprotective effects on SK-N-SH cells. J. Neurosci. 17:511-515.Google Scholar
  105. 105.
    Mooradian, A. D. 1993. Antioxidant properties of steroids. J. Steroid Biochem. Molec. Biol. 45:509-511.Google Scholar
  106. 106.
    Behl, C., Skutella, T., Lezoualc'h, F., Post, A., Widmann, M., Newton, C. J., and Holsboer, F. 1997. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mole. Pharm. 51:535-541.Google Scholar
  107. 107.
    Behl, C., Widmann, M., Trapp, T., and Holsboer, F. 1998. 17 beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem. Biophys. Res. Comm. 216:473-482.Google Scholar
  108. 108.
    Birge, S. J. 1994. The Role of Estrogen Deficiency in the Aging Central Nervous System. In Lobo, R. A., ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. New York, Raven Press, Ltd., 153-157. Notes: Chapter Num: 14.Google Scholar
  109. 109.
    Henderson, V. W., Paganini-Hill, A., Emanuel, C. K., Dunn, M. E., and Buckwalter, J. G. 1994. Estrogen Replacement Therapy in Older Women: Comparisons between Alzheimer's Disease Cases and Nondemented Control Subjects. Archives of Neurology 51:896-900.Google Scholar
  110. 110.
    Paganini-Hill, A. and Henderson, V. W. 1994. Estrogen Deficiency and Risk of Alzheimer's Disease in Women. American Journal of Epidemilogy 3:3-16.Google Scholar
  111. 111.
    Henderson, V. W., Watt, L., and Buckwalter, J. G. 1996. Cognitive Skills Associated With Estrogen Replacement In Women With Alzheimer's Disease. Psychoneuroendocrinology 12:421-430.Google Scholar
  112. 112.
    Yaffe, K., Sawaya, G., Lieberburg, I., and Grady, D. 1998. Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. JAMA 279:688-695.Google Scholar
  113. 113.
    Joseph, J. A., Shukitt-Hale, B., Denisova, N. A., Prior, R. L., Cao, G., Martin, A., Taglialatela, G., and Bickford, P. C. 1998. Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J. Neurosci. 18: 8047-8055.Google Scholar
  114. 114.
    Le Bars, P. L., Katz, M. M., Berman, N., Itil, T. M., Freedman, A. M., and Schatzberg, A. F. 1997. A placebo-controlled, double-blind, randomized trial of an extract of Ginko biloba for dementia. JAMA 278:1327-1332.Google Scholar
  115. 115.
    Patisaul, H. B., Whitten, P. L., and Young, L. J. 1999. Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17β-estradiol and the phytoestrogen, coumestrol. Mol. Brain Res. 67:165-171.Google Scholar
  116. 116.
    Nagata, C., Takatsuka, N., Inaba, S., Kawakami, N., and Shimizu, H. 1998. Effect of soymilk consumption on serum estrogen concentrations in premenopausal Japanese women. J. Natl. Cancer Inst. 90:1830-1835.Google Scholar
  117. 117.
    Morrison, R. S., Wenzel, H. J., Kinoshita, Y., Robbins, C. A., Donehower, L. A., and Schwartzkroin, P. A. 1996. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J. Neurosci. 16:1337-1345.Google Scholar
  118. 118.
    Xiang, H., Hochman, D. W., Saya, H., Fujiwara, T., Schwartzkroin, P. A., and Morrison, R. S. 1996. Evidence for p53-mediated modulation of neuronal viability. J. Neurosci. 16:6753-6765.Google Scholar
  119. 119.
    Kondo, T., Reaume, A. G., Huang, T.-T., Carlson, E., Murakami, K., Chen, S. F., Hoffman, E. K., Scott, R. W., Epstein, C. J., and Chan, P. H. 1997. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17:4180-4189.Google Scholar
  120. 120.
    Reagan, L. P., Magarinos, A. M., and McEwen, B. S. 1998. Molecular changes induced by stress in streptozotocin (STZ) diabetic rats. Society for Neuroscience Abstract.Google Scholar
  121. 121.
    Pouliot, W. A., Handa, R. J., and Beck, S. G. 1996. Androgen Modulates N-Methyl-D-Aspartate-mediated Depolarization in CA1 Hippocampal Pyramidal Cells. Synapse 23:10-19.Google Scholar
  122. 122.
    Grindley, K. E., Green, P. S., and Simpkins, J. W. 1997. Low concentrations of estradiol reduce β-amyloid (25-35) induced toxicity, lipid peroxidation and glucose utilization in human SKN-SH neuroblastoma cells. Brain Res. 778:158-165.Google Scholar
  123. 123.
    Kimonides, V. G., Khatibi, N. H., Sofroniew, M. V., and Herbert, J. 1998. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc. Nat. Acad. Sci. USA 95:1852-1857.Google Scholar
  124. 124.
    Bastianetto, S., Ramassamy, C., Poirier, J., and Quirion, R. 1999. Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Mol. Brain Res. 66:35-41Google Scholar
  125. 125.
    Ho, D. Y., Saydam, T. C., Fink, S. L., Lawrence, M. S., and Sapolsky, R. M. 1995. Defective herpes simplex virus vectors expressing the rat brain glucose transporter protect cultured neurons from necrotic insults. J. Neurochem. 65:842-850.Google Scholar
  126. 126.
    McEwen, B. S. 1999. The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J. Clin. Endocrinol. Metab. 84:1790-1797.Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Bruce S. McEwen
    • 1
  1. 1.Harold and Margaret Milliken Hatch Laboratory of NeuroendocrinologyRockefeller UniversityNew York

Personalised recommendations