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Background : The neuroprotective effects of duloxetine and neurodegenerative effects of methamphetamine have been shown in previous studies, but their exact mechanism remain unclear. In the current study it involved molecular mechanisms of neuroprotective effects of duloxetine against methamphetamine induced neurodegeneration were clarified. Methods : About 40 adult male rats randomly were divided to 5 groups. Group 1 and 2, as control and methamphetamine treated, received normal saline and methamphetamine (10 mg/kg) respectively. Groups 3, 4 and 5 concurrently treated with methamphetamine and duloxetine at doses of 10, 20 and 30 mg/kg respectively. All treatments were undertaken for 21 days. On day 22 Open Field Test (OFT) were used to examine the level of motor activity disturbance and anxiety in animals. After that hippocampus was isolated from each rat and oxidative, antioxidant, inflammatory factors and also level or expression of total and phosphorylated forms of CREB and P‑CREB and BDNF proteins were measured. Results : Duloxetine in all mentioned doses could inhibit the effects of methamphetamine induced motor activity disturbance in MWM. Chronic abuse of methamphetamine could increase malondialdehyde (MDA), tumor necrosis factor‑Alpha (TNF‑ α ) and interleukine‑1beta (IL‑1 β ) while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and decreased CREB (both forms) and BDNF proteins, while duloxetine could prevent these malicious effects of methamphetamine. Conclusions : We conclude that P‑CREB/ BDNF signaling pathways might have critical role in duloxetine neuroprotective effects against methamphetamine induced neurodegeneration. Keyword : Duloxetine, methamphetamine, motor activity, neurodegeneration, P‑CREB/BDNF pathway

Background: Forced exercise can act as non-pharmacologic neuroprotective agent. In current study, we tried the involved molecular mechanisms of protective effects of forced exercise against methamphetamine induced neurodegeneration. Materials and Methods: Forty adult male rats were divided to Group 1 and 2 which received normal saline and methamphetamine (10 mg/kg) respectively for 30 days. Groups 3, 4 and 5 were treated with methamphetamine for first 15 days and then were treated by forced exercise, bupropion (20 mg/kg/day) or combination of them for the following 15 days. Between 26th and 30th days, Morris Water Maze (MWM) was used to evaluate the cognition. On day 31, hippocampus was isolated from each rat and oxidative, antioxidant and inflammatory factors also the level of total and phosphorylated forms of cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) proteins were also evaluated. Results: Chronic abuse of methamphetamine could decreases cognition and increase malondialdehyde (MDA), Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities all these changes was significant (P < 0.001) in compared to control group while treatment with bupropion, forced exercise and bupropion in combination with forced exercise could prevent all these malicious effects of methamphetamine (P < 0.001). Bupropion, forced exercise and bupropion in combination with forced exercise could activate CREB (both forms) and activates BDNF proteins' expression with P < 0.001 in methamphetamine treated rats. Conclusions: P-CREB/BDNF signaling pathways might have critical role in forced exercise protective effects against methamphetamine induced neurodegeneration.