en Neurophysiology/Pharmacology Neurophysiology/Pharmacology Experimental research article Experimental research article <p><span style="font-size:12px;"><span style="font-family:Arial;"><strong>Introduction:</strong> Methamphetamine (Meth) is a highly addictive psychostimulant and induces neuroinflammatory responses. Melatonin is a neurohormone that has protective effects and reduces inflammation in the central nervous system. Our study focused on the melatonin effect on memory impairment, NLRP3/IL-1&beta; axis, and gasdermin D and caspase-1 expression in the hippocampus of a rat model of Meth use.<br /> <strong>Methods: </strong>Meth and melatonin were administered to the rats for 21 consecutive days. The memory was evaluated using alternation behavior in Y-maze. NLRP3 and IL-1&beta; were assessed by western blotting and ELISA, respectively. &nbsp;Gasdermin D and caspase-1 expression levels were evaluated using qRT-PCR.<br /> <strong>Results: </strong>The NLRP3 and IL-1&beta; were elevated in the hippocampus following Meth injection. Moreover, Meth increased gasdermin D and caspase-1 expression levels. After 21 days of Meth use, memory impairment was seen in the Y-maze test. Melatonin significantly improved memory and decreased the expression of NLRP3, IL-1&beta;, gasdermin D, and caspase-1 in the hippocampus.<br /> <strong>Conclusion: </strong>Our study revealed that inflammasome formation and pyroptosis pathway are involved in Meth-induced neurotoxicity. Melatonin may be a potential treatment against neurotoxicity and cognitive disorders caused by Meth.</span></span></p> Methamphetamine, Melatonin, NLRP3, Interlukine-1β, Working memory, Pyroptosis 430 439 http://ppj.phypha.ir/browse.php?a_code=A-10-2340-1&slc_lang=en&sid=1 Seyed Khalil Rashidi m.kh.rashidi@gmail.com 3200319475328460038139 3200319475328460038139 No Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran Mitra Ansari Dezfouli mitraansari84@gmail.com 3200319475328460038140 0000000284968750 Yes Department of Neurology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Fariba Khodagholi khodagholi@sbmu.com 3200319475328460038141 3200319475328460038141 No Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mehdi Dadashpour dadashpourmehdi1400@gmail.com 3200319475328460038142 3200319475328460038142 No Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran Ali Akbar Shabani aashaebani@yahoo.com 3200319475328460038143 0000000257469980 No Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran