DHEA, together with DHEAS, is the most abundant steroid in the blood of young adult humans. Levels in humans decline with age and during certain types of illness or stress. We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists N-methyl-D-aspartic acid (NMDA) both in vitro and in vivo or ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Pre-treatment with DHEA (10-100 nM for 6-8 h) protected primary hippocampal cultures from embryonic day 18 (E18) embryos against NMDA-induced toxicity (0.1, 1, 10, and 50 mM). DHEA added either with NMDA (1 mM) or 1 h later had lesser, but still significant, protective actions. DHEAS also reduced NMDAinduced toxicity (1 mM), although the lowest effective dose of DHEAS (100 nM) was higher than that of DHEA (10 nM). DHEA (100 nM) protected cultured neurons against the neurotoxic actions of either AMPA (25 M) or kainic acid (1 mM) as well. In vivo, s.c. pellets of DHEA, which resulted in plasma levels that resembled those in young adult humans, protected hippocampal CA1͞2 neurons against unilateral infusions of 5 or 10 nmol of NMDA. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage. Levels of DHEA, together with DHEAS, peak at Ϸ20 years of age in humans and then decline ineluctably to reach values of 20-30% at Ϸ70-80 years of age (1). DHEA(S) levels also are reduced by intercurrent stressful events such as an episode of major depressive disorder (2, 3) or systemic disease (4, 5). Recent evidence shows that DHEA and DHEAS have direct actions on the brain, acting as allosteric modulators of ␥-aminobutyric acid type A receptors (6), interacting with voltagegated Ca 2ϩ channels in CA1 hippocampal neurons (7), reducing aggression, and improving memory in mice (8, 9). The functional and clinical significance of age-related or stressinduced declines in DHEA or DHEAS for neural function is not understood. Both age and stress are associated with neuronal vulnerability to degeneration (10). We have found that DHEA or DHEAS can prevent or reduce the neurotoxic actions of the glutamate agonist N-methyl-D-aspartic acid (NMDA) in the hippocampus both in vitro and in vivo, as well as that of two other glutamate receptor agonists, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults (11-13), these results suggest that decreased DHEA(S) levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.

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