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NEUROPHARMACOLOGY

-Estradiol, Dehydroepiandrosterone, and Dehydroepiandrosterone Sulfate Protect against N-Methyl-D-aspartate-Induced Neurotoxicity in Rat Hippocampal Neurons by Different Mechanisms

Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Japan (K.K., S.M., S.Y.); and Laboratory of Psycho-oncology, Institute of Clinical Research, National Hospital Organization Kure Medical Center, Hiroshima, Japan (M.T.)

We examined neuroprotective effects of -estradiol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in primary cultured rat hippocampal neurons. All three steroids demonstrated neuroprotective effects. Time-course studies revealed that steroid cotreatment for only 15 min at the same time as exposure to NMDA, but neither pretreatment nor addition of steroids for 24 h after NMDA-mediated neuroprotective effects. This indicates that short-term actions of these steroids are critical for this process. Acute treatment with -estradiol dose dependently inhibited NMDA-induced intracellular Ca²⁺ increases, which strongly correlated with its neuroprotective effect via L-type voltage-gated calcium channels. Acute treatment with DHEA, but not with DHEA-S, significantly inhibited nitric oxide (NO) production and Ca²⁺-sensitive NO synthase (NOS) activity caused by NMDA stimulation. An NOS inhibitor, N^G-monomethyl-L-arginine acetate was also protective against NMDA-induced neurotoxicity. These data indicate that -estradiol may exert neuroprotective effects mainly by reducing Ca²⁺ increases but that DHEA may act by inhibiting NOS activity. Treatment with the -1 receptor (Sig-1R) antagonists rimcazole or BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride) partially, but significantly, reversed the neuroprotective effect of DHEA-S against NMDA-induced neurotoxicity, whereas muscimol, a GABA-A-receptor agonist, did not. This suggests that the neuroprotective effect of DHEA-S may be mediated via Sig-1R, at least in part. Together, our data suggest that the neurosteroid family members -estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.

Address correspondence to: Dr. Shigeto Yamawaki, Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: yamawaki{at}hiroshima-u.ac.jp

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