Abstract
Methamphetamine (Meth) is an addictive psychostimulant abused worldwide. Ample evidence indicate that chronic abuse of Meth induces neurotoxicity via microglia-associated neuroinflammation and the activated microglia present in both Meth-administered animals and human abusers. The development of anti-neuroinflammation as a therapeutic strategy against Meth dependence promotes research to identify inflammatory pathways that are specifically tied to Meth-induced neurotoxicity. Currently, the exact mechanisms for Meth-induced microglia activation are largely unknown. NLRP3 is a well-studied cytosolic pattern recognition receptor (PRR), which promotes the assembly of the inflammasome in response to the danger-associated molecular patterns (DAMPs). It is our hypothesis that Meth activates NLRP3 inflammasome in microglia and promotes the processing and release of interleukin (IL)-1β, resulting in neurotoxic activity. To test this hypothesis, we studied the effects of Meth on IL-1β maturation and release from rat cortical microglial cultures. Incubation of microglia with physiologically relevant concentrations of Meth after lipopolysaccharide (LPS) priming produced an enhancement on IL-1β maturation and release. Meth treatment potentiated aggregation of inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), induced activation of the IL-1β converting enzyme caspase-1 and produced lysosomal and mitochondrial impairment. Blockade of capase-1 activity, lysosomal cathepsin B activity or mitochondrial ROS production by their specific inhibitors reversed the effects of Meth, demonstrating an involvement of inflammasome in Meth-induced microglia activation. Taken together, our results suggest that Meth triggers microglial inflammasome activation in a manner dependent on both mitochondrial and lysosomal danger-signaling pathways.