Mechanism-based novel antidotes for organophosphate neurotoxicity.
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abstract
This article describes current pursuits for developing novel antidotes for organophosphate (OP) intoxication. Recent mechanistic studies of benzodiazepine-resistant seizures have key consequences for victims of OP pesticide and nerve agent attacks. We uncovered why current therapies are not able to stop the OP-induced seizures and brain cell death and what type of drug might be better. OP exposure down regulates critical inhibitory GABA-A receptors, kills neurons, and causes massive neuroinflammation that will cause more neuronal death, which causes the problem of too few benzodiazepine receptors. The loss of inhibitory interneurons creates a self-sustaining seizure circuit and refractory status epilepticus. Thus, there is an urgent need for mechanism-based, new antidotes for OP intoxication. We have discovered neurosteroids as next-generation anticonvulsants superior to midazolam for the treatment of OP poisoning. Neurosteroids that activate both extrasynaptic and synaptic GABA-A receptors have the potential to stop seizures more effectively and safely than benzodiazepines. In addition, neurosteroids confers robust neuroprotection by reducing neuronal injury and neuroinflammation. The synthetic neurosteroid ganaxolone is being considered for advanced development as a future anticonvulsant for nerve agents. Experimental studies shows striking efficacy of ganaxolone and its analogs in OP exposure models. They are also effective in attenuating long-term neuropsychiatric deficits caused by OP exposure. Overall, neurosteroids represent rational anticonvulsants for OP intoxication, even when given late after exposure.
