International Journal of Preventive Medicine (Int J Prev Med)2008-780210112020022521862186ENSchool of Behavioral Sciences and Mental Health (Tehran Institute of Psychiatry), TehranDepartment of Pharmacology, School of Medicine, Iran University of Medical Sciences, TehranDepartment of Chemistry, Faculty of Sciences, University of Zanjan 45371‑38791, ZanjanResearch Center for Addiction and Risky Behaviors (ReCARB), Iran Psychiatric Center, Iran University of Medical Sciences, TehranDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, TehranDepartment of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran20200216<p><span class="fontstyle0"><strong>Background</strong>: </span><span class="fontstyle2">The neuroprotective effects of duloxetine and neurodegenerative effects of<br />methamphetamine have been shown in previous studies, but their exact mechanism remain unclear.<br />In the current study it involved molecular mechanisms of neuroprotective effects of duloxetine<br />against methamphetamine induced neurodegeneration were clarified. </span></p><p><span class="fontstyle0"><strong>Methods</strong>: </span><span class="fontstyle2">About 40 adult<br />male rats randomly were divided to 5 groups. Group 1 and 2, as control and methamphetamine<br />treated, received normal saline and methamphetamine (10 mg/kg) respectively. Groups 3, 4 and<br />5 concurrently treated with methamphetamine and duloxetine at doses of 10, 20 and 30 mg/kg<br />respectively. All treatments were undertaken for 21 days. On day 22 Open Field Test (OFT) were used<br />to examine the level of motor activity disturbance and anxiety in animals. After that hippocampus<br />was isolated from each rat and oxidative, antioxidant, inflammatory factors and also level or<br />expression of total and phosphorylated forms of CREB and P‑CREB and BDNF proteins were<br />measured. </span></p><p><span class="fontstyle0"><strong>Results</strong>: </span><span class="fontstyle2">Duloxetine in all mentioned doses could inhibit the effects of methamphetamine<br />induced motor activity disturbance in MWM. Chronic abuse of methamphetamine could increase<br />malondialdehyde (MDA), tumor necrosis factor‑Alpha (TNF‑</span><span class="fontstyle3">α</span><span class="fontstyle2">) and interleukine‑1beta (IL‑1</span><span class="fontstyle3">β</span><span class="fontstyle2">) while<br />caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione<br />reductase (GR) activities and decreased CREB (both forms) and BDNF proteins, while duloxetine<br />could prevent these malicious effects of methamphetamine. </span></p><p><span class="fontstyle0"><strong>Conclusions</strong>: </span><span class="fontstyle2">We conclude that P‑CREB/<br />BDNF signaling pathways might have critical role in duloxetine neuroprotective effects against<br />methamphetamine induced neurodegeneration.<br /></span></p><p><span class="fontstyle0" style="color: #00652e;"><strong>Keyword</strong>: </span><span class="fontstyle4">Duloxetine, methamphetamine, motor activity, neurodegeneration, P‑CREB/BDNF<br />pathway</span></p>http://ijpm.mui.ac.ir/index.php/ijpm/article/view/2186http://ijpm.mui.ac.ir/index.php/ijpm/article/download/2186/717718075