NEUROPROTECTION BY DEHYDROEPIANDROSTERONE-SULFATE - ROLE OF AN NF-KAPPA-B-LIKE FACTOR

LEVELS of dehydroepiandrosterone (DHEA) and its sulfated derivative (D HEA-S) decline during aging and reach even lower levels in Alzheimer's disease (AD). Previously published effects of DHEA and DHEA-S on unch allenged neuronal survival led us to test them in an excitotoxicity pa radigm. While DHEA-S protected hippocampal neurons against glutamate, little protection was observed with equivalent doses of DHEA itself. T his differential neuroprotection was consistent with the ability of DH EA-S (but not DHEA) to elevate a kappa B-dependent transcription facto r activity, a phenomenon we previously have connected with neuroprotec tion. Furthermore, suppression of kappa B DNA-binding by 'decoy' oligo nucleotides blocked the neuroprotective activity of DHEA-S. These find ings imply that age-related declines in the availability of DHEA-S cou ld exacerbate neurotoxicity, and the data suggest that therapeutic gai ns may be obtained with pharmacological manipulation of kappa B-depend ent transcription in neurons.