en Cellular and molecular Neuroscience Cellular and molecular Neuroscience Original Original <strong>Introduction</strong>: The neuroprotective impact of curcumin and the role of CREB (Cyclic AMP Response Element Binding protein)-BDNF (Brain-Derived Neurotrophic Factor) signaling pathway was evaluated in Methamphetamine (METH)-induced neurodegeneration in rats.<br> <strong>Methods</strong>: Sixty adult male rats were randomly divided into 6 groups. While normal saline and 10 mg/kg METH were administered intraperitoneally in groups 1 and 2, groups 3, 4, 5, and 6 received METH (10 mg/kg) and curcumin (10, 20, 40, and 80 mg/kg, respectively) simultaneously. Morris water maze test was administered, and oxidative hippocampal, antioxidant, inflammatory, apoptotic, and CREB and BDNF were assessed.<br> <strong>Results</strong>: We found that METH disturbs learning and memory. Concurrent curcumin therapy (40 and 80 mg/kg) decreased cognitive disturbance caused by METH. Multiple parameters, such as lipid peroxidation, the oxidized form of glutathione, interleukin 1 beta, tumor necrosis factor-alpha, and Bax were increased by METH therapy, while the reduced type of glutathione, Bcl-2, P-CREB, and BDNF concentrations in the hippocampus were decreased.&nbsp;<br> <strong>Conclusion</strong>: Different doses of curcumin adversely attenuated METH-induced apoptosis, oxidative stress, and inflammation but enhanced the concentrations of P-CREB and BDNF. The neuroprotection caused by curcumin against METH-induced neurodegeneration is mediated through P-CREB-BDNF signaling pathway activation. Methamphetamine, Curcumin, Neurodegeneration, Cyclic AMP response element binding protein, Brain-derived neurotrophic factor 325 338 http://bcn.iums.ac.ir/browse.php?a_code=A-10-1176-3&slc_lang=en&sid=1 Mina Gholami 13700319475328460035954 13700319475328460035954 No Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Farzad Hozuri 13700319475328460035955 13700319475328460035955 No Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Setayesh Abdolkarimi 13700319475328460035956 13700319475328460035956 No Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Mahsa Mahmoudi 13700319475328460035957 13700319475328460035957 No Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Majid Motaghinejad dr.motaghinejad6@gmail.com 13700319475328460035958 13700319475328460035958 Yes Research Center for Addiction and Risky Behaviors (ReCARB), Iran Psychiatric Center, Iran University of Medical Sciences, Tehran, Iran. Sepideh Safari 13700319475328460035959 13700319475328460035959 No Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran. Samira Sadr 13700319475328460035960 13700319475328460035960 No Department of Research and Development, Parsian-Exir-Aria Pharmaceutical Company, Tehran, Iran.