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Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging
- Source :
- Annals of the New York Academy of Sciences. 1088
- Publication Year :
- 2006
-
Abstract
- The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age-related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents. Indeed, DHEA(S) protects rat hippocampal neurons against NMDA-induced excitotoxicity, whereas Allo ameliorates NMDA-induced excitotoxicity in human neurons. These steroids exert also a protective role on the sympathetic nervous system. Indeed, DHEA, DHEAS, and Allo protect chromaffin cells and the sympathoadrenal PC12 cells (an established model for the study of neuronal cell apoptosis and survival) against serum deprivation-induced apoptosis. Their effects are time- and dose-dependent with EC(50) 1.8, 1.1, and 1.5 nM, respectively. The prosurvival effect of DHEA(S) appears to be NMDA-, GABA(A)- sigma1-, or estrogen receptor-independent, and is mediated by G-protein-coupled-specific membrane binding sites. It involves the antiapoptotic Bcl-2 proteins, and the activation of prosurvival transcription factors CREB and NF-kappaB, upstream effectors of the antiapoptotic Bcl-2 protein expression, as well as prosurvival kinase PKCalpha/beta, a posttranslational activator of Bcl-2. Furthermore, they directly stimulate biosynthesis and release of neuroprotective catecholamines, exerting a direct transcriptional effect on tyrosine hydroxylase, and regulating actin depolymerization and submembrane actin filament disassembly, a fast-response cellular system regulating trafficking of catecholamine vesicles. These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.
- Subjects :
- medicine.medical_specialty
Aging
Neuroactive steroid
Neuroimmunomodulation
Excitotoxicity
Dehydroepiandrosterone
Apoptosis
Pregnanolone
CREB
medicine.disease_cause
Neuroprotection
General Biochemistry, Genetics and Molecular Biology
chemistry.chemical_compound
History and Philosophy of Science
Internal medicine
medicine
Animals
Humans
Neurons
biology
Tyrosine hydroxylase
General Neuroscience
Allopregnanolone
Endocrinology
nervous system
chemistry
biology.protein
Catecholamine
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- ISSN :
- 00778923
- Volume :
- 1088
- Database :
- OpenAIRE
- Journal :
- Annals of the New York Academy of Sciences
- Accession number :
- edsair.doi.dedup.....03a00c772d1a78e2dc1139e890578995