Allopregnanolone-mediated protective effects of progesterone on tributyltin-induced neuronal injury in rat hippocampal slices

摘要

Increasing evidence shows that progesterone, a neuroactive steroid, has protective actions in central nervous system, but there is little evidence to show the protective mechanism of progesterone on neu-rotoxicity induced by environmental chemicals. In this study, we examined the effects of progesterone on neuronal injury induced by tributyltin (TBT) in rat hippocampal slices. Treatment with progesterone dose-dependently suppressed hippocampal neuronal injury induced by TBT. The neuroprotective action of progesterone was completely canceled with pretreatment by finasteride, a 5alpha-reductase inhibitor, but it was not affected by mifepristone, a progesterone receptor antagonist, or by SU-10603, a cytochrome P450 17alpha inhibitor. The content of allopregnanolone in the slices was significantly increased by treatment with progesterone, and this increment was greatly suppressed with a pretreatment of finasteride. Treatment with allopregnanolone attenuated neuronal injury induced by TBT in a dose-dependent manner. The neuroprotective effects not only of progesterone but also of allopregnanolone were canceled by bicuculline, a potent gamma-aminobutyric acid A (GABAA) receptor antagonist. Pretreatment with mus-cimol, a GABAa receptor agonist, attenuated hippocampal neuronal injury elicited by TBT. Taken together, allopregnanolone converted from progesterone in hippocampal slices could protect neurons from TBT-induced neurotoxicity due to a GABAa receptor-dependent mechanism. One of the physiological roles of neuroactive steroids might be neuroprotection from environmental chemicals.