Sarin-Induced Neuroinflammation in Mouse Brain is Attenuated by the Caspase Inhibitor Q-VD-Oph.

Organophosphates cause hyperstimulation of the CNS, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of pro-inflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of Q-VD-OPh, a pan caspase inhibitor to attenuate neuro-inflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control Q-VE-OPh, sacrificed at 2 and 14 day time points, followed by removal of the amygdala and hippocampus. A Bio-Rad® 23-Plex cytokine analysis was completed on each tissue. The results suggest that exposure to sarin induced a dramatic increase in IL-1b and 6 other cytokines and a decrease in 2 of the 23 cytokines at 2 days in the amygdala compared to controls. Q-VD-OPh attenuated these changes at the 2 day time point. At 14 days, 6 of these cytokines were still significantly different from controls. Hippocampus was less affected at both time points. Diazepam, a neuroprotective drug against nerve agents, caused an increase in several cytokines, but did not have a synergistic effect with Q-VD-OPh. Treatment of sarin exposure with apoptosis inhibitors appears to be a worthwhile approach for further testing as a comprehensive counteragent against OP exposure. Significance Statement A pan inhibitor of caspases (Q-VD-OPh) was proposed as a potential antidote for sarin-induced neuroinflammation by reducing the level of inflammation via inflammasome caspase inhibition. Q-VD-OPh added at 30 minutes post-sarin exposure attenuated the inflammatory response of multiple cytokines and chemokines in the amygdala and hippocampus, two regions sensitive to OP exposure. Apoptotic marker reduction at 2 and 14 days further supports further testing of inhibitors of apoptosis as a means to lessen extended OP toxicity in the brain.