Neuroprotection by dehydroepiandrosteronesulfate

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Abstract
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.