beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms

J Pharmacol Exp Ther. 2004 Oct;311(1):237-45. doi: 10.1124/jpet.104.067629. Epub 2004 Jun 2.

Abstract

We examined neuroprotective effects of beta-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 beta-estradiol dose dependently inhibited NMDA-induced 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-S, 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-induced neurotoxicity. These data indicate that beta-estradiol 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-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 beta-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Dehydroepiandrosterone / pharmacology
  • Dehydroepiandrosterone Sulfate / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Drug Interactions
  • Estradiol / pharmacology
  • Hippocampus / cytology*
  • N-Methylaspartate / antagonists & inhibitors
  • N-Methylaspartate / pharmacology*
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Nifedipine / pharmacology
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nitroprusside / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / metabolism
  • Receptors, sigma / metabolism
  • Sigma-1 Receptor

Substances

  • Neuroprotective Agents
  • Receptors, GABA-A
  • Receptors, sigma
  • Nitroprusside
  • Nitric Oxide
  • Dehydroepiandrosterone
  • Estradiol
  • Dehydroepiandrosterone Sulfate
  • N-Methylaspartate
  • Dizocilpine Maleate
  • Nitric Oxide Synthase
  • Nifedipine
  • Calcium