Neuroprotective effects of steroid analogues on P19-N neurons.
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.
Xilouri
Maria
M
Department of Animal & Human Physiology, School of Biology, Faculty of Sciences, University of Athens, Panepistimiopolis, 15784 Athens, Greece.
Avlonitis
Nicolaos
N
Calogeropoulou
Theodora
T
Papazafiri
Panagiota
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D051058:Oncogene Protein v-akt / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D013256:Steroids; D003687:Dehydroepiandrosterone; D016202:N-Methylaspartate; D011280:Pregnanolone; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt