Protective effects of neurosteroids against NMDA-induced seizures and lethality in mice.

The effects of some neurosteroids on N-methyl-D-aspartic acid (NMDA)-induced seizures were examined in mice. Intraperitoneal (i.p.) administration of 5 alpha-pregnan-3 alpha-ol-20-one (5, 10 and 20 mg/kg). 5 beta-pregnan-3 alpha-ol-20-one (10 and 20 mg/kg), 5 alpha-pregnan-3 alpha-ol-11,20-dione (15 mg/kg), 5 alpha-androstan-3 alpha-ol-17-one (10 mg/kg) and dehydroepiandrosterone sulfate (25 mg/kg) significantly increased the dose of NMDA necessary to induce clonic convulsions in 50% of the tested animals (CD50). Furthermore, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 alpha-pregnan-3 alpha-ol-11,20-dione and 5 alpha-androstan-3 alpha-ol-17-one also protected the mice against NMDA-induced mortality. Importantly, it is only at the highest doses that neurosteroids impair motor performance of the animals, as estimated by a rotorod equilibrium procedure. The other neurosteroids tested, such as 5 alpha-pregnan-3 beta-ol-20-one (5-20 mg/kg), 5 alpha-pregnan-3 alpha,21-diol-20-one (10 and 15 mg/kg), 5 alpha-pregnan-3,20-dione (15 mg/kg) and pregnenolone sulfate (12.5-100 mg/kg) had no significant effects on the measured parameters. In another set of experiments, we evaluated the effects of neurosteroids on D-[3H]-aspartate release from rat hippocampal slices. None of the neurosteroids tested exerted a significant effect on basal D-[3H]-aspartate release. On the other hand, K(+)-stimulated D-[3H]-aspartate release was significantly attenuated by 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, alphaxalone, pregnenolone sulfate and dehydroepiandrosterone sulfate. The effect of 5 alpha-pregnan-3 alpha-ol-20-one was the most potent and was distinctly concentration-dependent, whereas the other compounds were effective only at the highest concentrations used. The above results indicate that some neurosteroids administered in non-sedative doses can protect mice against NMDA-induced seizures and mortality; furthermore, they inhibit D-[3H]-aspartate release in rat hippocampal slices.