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Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders pp 217–225Cite as

Dehydroepiandrosterone, as Endogenous Inhibitor of Neuronal Cell Apoptosis: Potential Therapeutic Implications in Neurodegenerative Diseases

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Dehydroepiandrosterone (DHEA) is synthesized in the adrenals and the brain. Additionally, DHEA is produced at high concentrations in the human embryo enhancing neuronal development. Its production rate and levels in serum, brain and adrenals decrease gradually with advancing age. This decline was associated to age-related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA against noxious agents. This hypothesis is substantiated by experimental findings showing that DHEA protect neural crest derived cells against serum deprivation-induced apoptosis with EC50 1.8 nM. This potent antiapoptotic effect of DHEA is mediated by G-protein coupled specific membrane binding sites, the subsequent activation of prosurvival kinases Src and PKC and transcription factors CREB and NF-κB, upstream effectors of the antiapoptotic Bcl-2 proteins. These findings suggest that DHEA may act as an endogenous neuroprotective factor, during development and in adulthood. The decline of DHEA levels during ageing may leave the brain unprotected against neurotoxic challenges. The DHEA specific membrane binding sites conferring neuroprotection offer a new target for developing synthetic DHEA analogs with antiapoptotic and neuroprotective properties, deprived of endocrine toxicity.

Keywords

  • DHEA
  • apoptosis
  • neurons
  • neuroprotection

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References

  1. Orentreich N, Brind JL, Rizer RL, et al. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59:551–555.

    PubMed  CrossRef  CAS  Google Scholar 

  2. Be’langer A, Candas B, Dupont A, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year old men. J Clin Endocrinol Metab 1994; 79:1086–1090.

    CrossRef  Google Scholar 

  3. Wolkowitz OM, Epel, ES, Reus VI. Stress hormone-related psychopathology: pathophysiological and treatment implications. World J Biol Psychiatry 2001; 2:115–143.

    PubMed  CAS  CrossRef  Google Scholar 

  4. Straub RH, Lehle K, Herfarth H, Weber, et al. Dehydroepiandrosterone in relation to other adrenal hormones during an acute inflammatory stressful disease state compared with chronic inflammatory disease: role of interleukin-6 and tumour necrosis factor. Eur J Endocrinol 2002; 146:365–374.

    PubMed  CrossRef  CAS  Google Scholar 

  5. Sapolsky RM. Stress, the aging brain and the mechanism of neuron death. Cambridge, MA: MIT, 1992.

    Google Scholar 

  6. Seals DR, Esler M. Human ageing and the sympathoadrenal system. J Physiol 2000; 528:407–417.

    PubMed  CrossRef  CAS  Google Scholar 

  7. Esler M, Lambert G, Kaye D, et al. Influence of ageing on the sympathetic nervous system and adrenal medulla at rest and during stress. Biogerontology 2002; 3:45–49.

    PubMed  CrossRef  CAS  Google Scholar 

  8. Bastianetto S, Ramassamy C, Poirier, et al. Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res 1999; 66:35–41.

    PubMed  CrossRef  CAS  Google Scholar 

  9. Cardounel A, Regelson W, Kalimi M. Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 1999; 22:145–149.

    CrossRef  Google Scholar 

  10. Lapchak PA, Chapman DF, Nunez SY, et al. Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors. Stroke 2000; 31:1953–1956.

    PubMed  CAS  Google Scholar 

  11. Kimonides VG, Khatibi NH, Svendsen CN, et al. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 1998; 95:1852–1857.

    PubMed  CrossRef  CAS  Google Scholar 

  12. Weill-Engerer S, David JP, Sazdovitch V, et al. Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab 2002; 87:5138–5143.

    PubMed  CrossRef  CAS  Google Scholar 

  13. Schumacher M, Weill-Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 2003; 71:3–29.

    PubMed  CrossRef  CAS  Google Scholar 

  14. Belanger N, Gregoire L, Bedard P, et al. Estradiol and dehydroepiandrosterone potentiate levodopa-induced locomotor activity in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine monkeys. Endocrine 2003; 1:97–101.

    CrossRef  Google Scholar 

  15. Belanger N, Gregoire L, Bedard PJ, et al. DHEA improves symptomatic treatment of moderately and severely impaired MPTP monkeys. Neurobiol Aging 2006; 11:1684–1693.

    CrossRef  CAS  Google Scholar 

  16. Charalampopoulos I, Tsatsanis C, Dermitzaki E, et al. Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal cells against apoptosis, via Bcl-2 antiapoptotic proteins. Proc Natl Acad Sci USA 2004; 101:8209–8214.

    PubMed  CrossRef  CAS  Google Scholar 

  17. Riccio A, Ahn S, Davenport CM, et al. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999; 286:2358–2361.

    PubMed  CrossRef  CAS  Google Scholar 

  18. Tamatani M, Che YH, Matsuzaki H, et al. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem 1999; 274:8531–8538.

    PubMed  CrossRef  CAS  Google Scholar 

  19. Ruvolo P, Deng X, Carr B, et al. A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 1998; 273:25436–25442.

    PubMed  CrossRef  CAS  Google Scholar 

  20. Charalampopoulos I, Alexaki VI, Lazaridis I, et al. G protein-associated, specific membrane binding sites mediate the neuroprotective effect of Dehydroepiandrosterone. FASEB J 2006; 20:577–579.

    PubMed  CAS  Google Scholar 

  21. Wooten M, Seibenhener ML, Neidich K, et al. Mapping of atypical protein kinase C within the nerve growth factor signaling cascade: relationship to differentiation and survival of PC12 cells. Mol Cell Biol 2000; 20:4494–4504.

    PubMed  CrossRef  CAS  Google Scholar 

  22. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005; 2:141–194.

    CrossRef  CAS  Google Scholar 

  23. Sapolsky RM. Glucocorticoid toxicity in the hippocampus: reversal by supplementation with brain fuels. J Neurosci 1986; 6:2240–2244.

    PubMed  CAS  Google Scholar 

  24. Sapolsky RM, Krey LC, McEwen BC. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Revs 1986; 7:284–301.

    CrossRef  CAS  Google Scholar 

  25. Marder K, Tang MX, Mejia H, et al. Risk of Parkinson’s disease among first-degree relatives: a community-based study. Neurology 1996; 47:155–160.

    PubMed  CAS  Google Scholar 

  26. Yang SH, Perez E, Cutright J, et al. Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model. J Appl Physiol 2002; 1:195–201.

    Google Scholar 

  27. Swaab DF, Raadsheer FC, Endert E, et al. Increased cortisol levels in aging and Alzheimer’s disease in postmortem cerebrospinal fluid. J Neuroendocrinol 1994; 6:681–687.

    PubMed  CrossRef  CAS  Google Scholar 

  28. Umegaki H, Ikari H, Nakahata H, et al. Plasma cortisol levels in elderly female subjects with Alzheimer’s disease: a cross-sectional and longitudinal study. Brain Res 2000; 881:241–243.

    PubMed  CrossRef  CAS  Google Scholar 

  29. Mattson M. Apoptosis in neurodegenerative disorders. Nature Rev Mol Cell Biol 2000; 1:120–129.

    CrossRef  CAS  Google Scholar 

  30. Kratnic S, Mechawar N, Reix S, et al. Molecular basis of programmed cell death involved in neurodegeneration. Trends Neurosci 2006; 28:670–676.

    Google Scholar 

  31. Forman MS, Trojanowski J, Lee V. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nature Med 2004; 10:1055–1063.

    PubMed  CrossRef  CAS  Google Scholar 

  32. Charalampopoulos I, Dermitzaki E, Vardouli L, et al. Dehydroepiandrosterone and allopregnanolone directly stimulate catecholamine production via induction of tyrosine hydroxylase and secretion by affecting actin polymerization. Endocrinology 2005; 146:3309–3318.

    PubMed  CrossRef  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Crete, Greece

    Ioannis Charalampopoulos Ph.D & Achille Gravanis Ph.D

  2. Department of Clinical Chemistry, University of Crete, Greece

    Christos Tsatsanis Ph.D & Andrew N. Margioris Ph.D

  3. Department of Experimental Endocrinology, University of Crete, Greece

    Elias Castanas M.D., Ph.D

Authors
  1. Ioannis Charalampopoulos Ph.D
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  2. Christos Tsatsanis Ph.D
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  3. Andrew N. Margioris Ph.D
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  4. Elias Castanas M.D., Ph.D
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  5. Achille Gravanis Ph.D
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Editor information

Editors and Affiliations

  1. Sha'ar Menashe Mental Health Center, Hadera, Israel

    Director Michael S. Ritsner M.D., Ph.D

  2. Geha Mental Health Center, Petah Tikva, Israel

    Director Abraham Weizman MD

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Charalampopoulos, I., Tsatsanis, C., Margioris, A.N., Castanas, E., Gravanis, A. (2008). Dehydroepiandrosterone, as Endogenous Inhibitor of Neuronal Cell Apoptosis: Potential Therapeutic Implications in Neurodegenerative Diseases. In: Ritsner, M.S., Weizman, A. (eds) Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6854-6_11

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