Pharmacological inhibition of mTOR activation by rapamycin attenuates neuroinflammation and spontaneous recurrent seizures in a rat model of acute organophosphate (OP) intoxication. by Peter Andrew

Peter Andrew

UC Davis | Michele Goss

Activity of the mTOR signaling pathway is elevated following acute intoxication with the organophosphorus pesticide, diisopropylfluorophosphate. Pharmacologic inhibition of mTOR following acute diisopropylfluorophosphate intoxication attenuates microglial activation. Our preliminary data also suggest the anti-epileptogenic effects of mTOR inhibition following organophosphate intoxication.

ABSTRACT

Acute organophosphate (OP) intoxication evokes status epilepticus and is associated with the development of chronic impairments such as spontaneous recurrent seizures (SRS). A growing body of evidence suggests that neuroinflammation may contribute to the development of chronic sequelae following acute OP intoxication. The mTOR signaling pathway is highly implicated in both immune and epileptogenic processes. Thus, we evaluated the activation of mTOR in a rat model of acute OP intoxication and probed the involvement of mTOR signaling in OP-induced neuroinflammation and epileptogenesis. Adult male Sprague-Dawley rats were acutely intoxicated with OP diisopropylfluorophosphate (DFP) and treated with standard medical countermeasures. mTOR activity is transiently enhanced in the hippocampus within 1 hour post exposure, returning to baseline at 3 days post exposure. Elevated mTOR activity is observed in microglial populations, suggesting the involvement of mTOR in DFP-induced neuroinflammation. Inhibition of mTOR attenuated DFP-induced microglial activation, further implicating mTOR activity in neuroinflammatory processes following acute OP intoxication. Moreover, preliminary data suggest that mTOR inhibition may suppress the development of SRS following DFP intoxication.

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