Effects of neurosteroids on kainate-induced seizures, neurotoxicity and lethality in mice

In the present study we examined effects of some neurosteroids on the kainate-induced seizures, lethality and neurotoxicity in mice. We found that 5 alpha-pregnan-3 alpha-ol-20-one (allopregnanolone; 10 and 20 mg/kg) markedly elevated CD50 for kainate-induced convulsions, whereas 5 beta-pregnan-3 alpha-ol-20-one, 5 alpha-pregnan-3 alpha-ol-11,20-dione, 5 alpha-androstan-3 alpha-ol-17-one, dehydroepiandrosterone sulfate, pregnenolone sulfate and aminosteroid (U-107) were ineffective in that test. Furthermore, 5 alpha-pregnan-3 alpha-ol-20-one (5-20 mg/kg), 5 beta-pregnan-3 alpha-ol-20-one (20 mg/kg) and 5 alpha-androstan-3 alpha-ol 17-one (10 and 20 mg/kg) decreased, while dehydroepiandrosterone sulfate (25 and 50 mg/kg) and pregnenolone sulfate (25 mg/kg) elevated the kainate-induced lethality in mice. A histological analysis showed that kainate caused a dose-dependent neuronal loss of CA1 and CA3 hippocampal fields. Of the neurosteroids tested, only allopregnanolone attenuated the kainate-induced neurotoxicity. The above data indicate that neurosteroids exert moderate effects on seizures and neurotoxic effects of kainate. On the other hand, neurosteroids with a GABAA receptor agonistic or antagonistic activity decrease or increase, respectively, the kainate-evoked lethality.