Neuroprotection by dehydroepiandrosterone-sulfate: role of an NFkappaB-like factor.
Levels of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) decline during aging and reach even lower levels in Alzheimer's disease (AD). Previously published effects of DHEA and DHEA-S on unchallenged neuronal survival led us to test them in an excitotoxicity paradigm. While DHEA-S protected hippocampal neurons against glutamate, little protection was observed with equivalent doses of DHEA itself. This differential neuroprotection was consistent with the ability of DHEA-S (but not DHEA) to elevate a kappaB-dependent transcription factor activity, a phenomenon we previously have connected with neuroprotection. Furthermore, suppression of kappaB DNA-binding by 'decoy' oligonucleotides blocked the neuroprotective activity of DHEA-S. These findings imply that age-related declines in the availability of DHEA-S could exacerbate neurotoxicity, and the data suggest that therapeutic gains may be obtained with pharmacological manipulation of kappaB-dependent transcription in neurons.
Mao
X
X
Department of Anatomy, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Barger
S W
SW
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D019579:Neocortex / Q000166:cytology* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051381:Rats; D013873:Thionucleotides; D014157:Transcription Factors / Q000378:metabolism
D016328:NF-kappa B; D018696:Neuroprotective Agents; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D014157:Transcription Factors; D018698:Glutamic Acid; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D003513:Cycloheximide