The Involvement of the NLRP3 Inflammasome and Pyroptosis in Methamphetamine-Induced Neurotoxicity: Effects on Hippocampal Structure and Memory

Abstract It is known that addictive doses of methamphetamine are neurotoxic; However, it remains unclear whether chronic administration of a lower dose (5 mg/kg) of methamphetamine causes similar neurotoxic effects. This study aimed to assess the effects of chronically administering 5 mg/kg of methamphetamine daily for 1, 2, and 3 weeks on spatial memory, object recognition, passive avoidance memory, hippocampal morphology, and neuroinflammation. Hippocampal morphology was assessed using Nissl stain. The expressions of NLRP3, ASC, and caspase-1 genes were measured as markers of neuroinflammation. Chronic administration of 5 mg/kg of methamphetamine led to significant activation of the inflammasomes (NLRP3, ASC, and caspase-1), resulting in pyramidal cell death in the hippocampus. It also caused impaired spatial memory and passive avoidance learning while leaving recognition memory unaffected. The observed pyramidal cell death is likely due to pyroptosis rather than apoptosis. In conclusion, prolonged administration of 5 mg/kg of methamphetamine was associated with severe inflammasome activation, pyramidal cell death, and mild cognitive decline. Contrary to previous beliefs, even lower doses of methamphetamine taken for an extended period can be neurotoxic.