Naturally occurring neurosteroids are potent allosteric modulators of
gamma-aminobutyric acid(A) receptor and through augmentation of
gamma-aminobutyric acid(A) receptor function, can protect neuronal cells
against N-methyl-D-aspartate receptor over-activation, ischemia and
traumatic brain injury. In this study, mouse P19 cells were induced to
differentiate into post-mitotic neurons and were subjected to
excitotoxicity in the presence of N-methyl-D-aspartate. Novel synthetic
analogues of the endogenous neurosteroids allopregnanolone and
dehydroepiandrostrone, inhibited excitotoxic cell death of P19-N
neurons, by directly maintaining the activation of PKB/Akt kinase, and
interfering with the intrinsic mitochondrial apoptotic pathway,
preserving cytochrome c in the mitochondria and Bax in the cytoplasm.
The efficiency and the potency of these neurosteroids were similar to
those of allopregnanolone and dehydroepiandrostrone. Their effects were
gamma-aminobutyric acid(A) receptor mediated, since they were abolished
in the presence of bicuculline, an antagonist of receptor’s function. In
addition, the synthetic compounds retained the ability to alter
gamma-aminobutyric acid(A) receptor subunit gene expression, but their
effects on transcriptional activity were less pronounced than those of
allopregnanolone and dehydroepiandrostrone. These results suggest that
synthetic neurosteroids may serve as potent, membrane acting,
neuroprotectants against N-methyl-D-aspartate receptor neurotoxicity on
neuronal cells. (c) 2007 Elsevier Ltd. All rights reserved
