Neuroprotective effects of neurosteroids against hypoxic-neurotoxicity in naive and benzodiazepine inverse agonist FG 7142-treated mice
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Objective: The present study investigates the effects of various neurosteroids on hypoxic stress-induced neurotoxicity in naive and FG 7142- treated mice. Methods: The extent of neurotoxicity after the slow induction of hypoxic stress was estimated by measuring the latency for the onset of tremors and convulsions followed by death. Results: Treatment with FG 7142 (5-20 mg/kg, i.p.) a banzodiazepine (BZD) inverse agonist, augmented the hypoxic neurotoxicity. Pretreatment with neurosteroid allopregnanolone (AP) offered a significant protection in both naive and FG 7142- treated mice. Dehydroeplanorosterone sulphate (DHEAS) had no protective effect. In contrast, pregnenolone sulphate (PS) at high doses significantly protected naive but not FG 7142-treated mice, while low doses are ineffective. Progesterone (PROG), a neurosteroid precursor, and 4-chlordiazepam (4'-CD) a mitochondrial diazepam binding inhibitor receptor (MDR) agonist, produced a dose-dependent protection of both naive and FG 7142-treated mice. The neuroprotective effects of AP, PROG and 4'-CD against hypoxic neurotoxicity were blocked by picrotoxin, a GABA-A chloride channel antagonist, but not by flumazenil, a selective BZD antagonist. However, picrotoxin failed to reverse the PS-induced hypoxic neuroprotection. The 4'-CD elicited protection was, however, reversed by PK11195, a partial MDR antagonist. In addition, triazolam, a short acting BZD, nifedipine, a calcium channel blocker, and dizoclipine, a non-competitive NMDA receptor blocker, also dose-dependently protected the mice from hypoxic neurotoxicity. Combined exposure of nifedipine and PS resulted in a significant additive effect in protecting the hypoxic neurotoxicity. Similarly, combined administration of nifedipine with PROG, 4'-CD or dizoclipine markedly augmented the protective effect of nifedipine. Further, the dizocilpine induced neuroprotection was blocked by DHEAS. Conclusion: These results show that neurosteroids AP, PS and PROG, and MDR ligand 4'-CD possess neuroprotective activity in hypoxic stress models. Further, the present study suggests a role for GABA-A and mitochondrial DBI receptors in the neurosteroidal alleviation of hypoxic neurotoxicity, and thus may have therapeutic implications in cerebral ischemia and neurodegenerative disorders.
