Inflammasome Inhibitor MCC950 Attenuates Methamphetamine-Induced Hippocampal Neurotoxicity and Aberrant Neurogenesis in a Sex-Dependent Manner.

Methamphetamine (METH) is a known proinflammatory agent; however, the impacts of inflammasomes on its neurotoxic effects are not fully understood. In the present study, we assessed the impact of prolonged METH administration on the hippocampal inflammasome profile in male and female mice and determined alterations of the inflammasome profile in response to METH. In addition to inflammasome activation, METH induced both systemic and hippocampal-specific inflammatory responses, leading to cognitive impairment, reduced hippocampal cell proliferation, and altered proteomic profiles. Importantly, the responses to METH exposure exhibited important sexual dimorphism. Treatment with inflammasome inhibitor MCC950 attenuated METH-induced inflammatory events; however, we also observed several off-target effects of this inhibitor affecting mouse anxiety-like behavior and cognitive function. Overall, our results indicate the preventive potential of MCC950 in METH-related neurotoxicity, while underscoring its limitations due to distinct sex-dependent differences in response to both METH and MCC950 and highlighting significant sexual dimorphism.