betA~1Estradiol,Dehydroepiandrosterone,and Dehydroepiandrosterone Sulfate Protect against N-Methyl-D-aspartate-lnduced Neurotoxiclty in Rat Hippocampal Neurons by Different Mechanisms

摘要

We examined neuroprotective effects of betA~1estradiol,dehydro-epiandrosterone(DHEA),and dehydroepiandrosterone sulfate(DHEA~1S)against N-methyl-D-aspartate(NMDA)-induced neu-rotoxicity 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~1mediated neuroprotective effects.This indicates that short-term actions of these steroids are critical for this process.Acute treatment with betA~1estradiol dose dependency inhibited NMDA~1induced intracellular Ca~(2+)increases,which strongly correlated with its neuroprotective effect via L-type voltage-gated calcium channels.Acute treatment with DHEA,but not with DHEA~1S,significantly inhibited nitric oxide(NO)production and Ca~(2+)-sensitive NO synthase(NOS)activity caused by NMDA stimulation.An NOS inhibitor,N~G-monomethyl-L-arginine acetate was also protective against NMDA~1induced neurotoxicity.These data indicate that betA~1estradiol may exert neuroprotective effects mainly by reducing Ca~(2+)increases but that DHEA may act by inhibiting NOS activity.Treatment with the sigma-1 receptor(Sig-1 R)antagonists rimcazole or BD1063(1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride)partially,but significantly,reversed the neuroprotective effect of DHEA~1S against NMDA~1 induced neurotoxicity,whereas muscimol,a GABA~1A~1receptor agonist,did not.This suggests that the neuroprotective effect of DHEA~1S may be mediated via Sig-1 R,at least in part.Together,our data suggest that the neurosteroid family members betA~1estradiol,DHEA,and DHEA~1S exert neuroprotective effects through different nongenomic mechanisms.