BACKGROUND Methamphetamine is a neuro-stimulant with neurodegenerative effects, and ambiguous mechanism of action. Metformin is an antidiabetic agent with neuroprotective properties but not fully understood mechanisms. The present study investigated the molecular basis of metformin neuroprotection against methamphetamine-induced neurodegeneration. BRIEF METHOD Sixty adult male rats were randomly divided into six groups: group 1 (received normal saline), group 2 (received 10 mg/kg of methamphetamine) and groups 3, 4, 5 and 6 [received methamphetamine (10 mg/kg) plus metformin (50, 75, 100 and 150 mg/kg) respectively]. Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST), Tail Suspension Test (TST) and Morris Water Maze (MWM) were used to assess the level of anxiety, depression and cognition in experimental animals. Also animals' hippocampus were isolated and oxidative stress and inflammatory parameters and expression of total and phosphorylated forms of cAMP response element binding (CREB), brain-derived neurotrophic factor (BDNF), protein kinase B (Akt) and glycogen synthase kinase 3 (GSK3) proteins were evaluated by ELISA method. RESULTS According to the data obtained, methamphetamine caused significant depression, anxiety, motor activity disturbances and cognition impairment in experimental animals. Metformin, in all used doses, decreased methamphetamine induced behavioral disturbances. Also chronic administration of methamphetamine could increase malondialdehyde (MDA), tumor necrosis factor-Alpha (TNF-α) and interleukine-1 beta (IL-1β) in rats, while caused reduction of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities. Metformin, especially in high doses, could prevent these malicious effects of methamphetamine. Also Metformin could activate CREB (both forms), BDNF and Akt (both forms) proteins' expression and inhibited GSK3 (both forms) protein expression in methamphetamine treated rats. SIGNIFICANCE According to obtained data, metformin could protect the brain against methamphetamine-induced neurodegeneration probably by mediation of CREB/BDNF or Akt/GSK3 signaling pathways. These data suggested that CREB/BDNF or Akt/GSK3 signaling pathways may have a critical role in methamphetamine induced neurotoxicity and/or neuroprotective effects of metformin.

中文翻译：

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二甲双胍对甲基苯丙胺引起的大鼠焦虑、抑郁、认知障碍和神经变性的保护作用：CREB/BDNF 和 Akt/GSK3 信号通路的作用。


背景技术甲基苯丙胺是一种神经兴奋剂，具有神经退行性作用，且作用机制不明确。二甲双胍是一种具有神经保护特性的抗糖尿病药物，但其机制尚不完全清楚。本研究调查了二甲双胍对甲基苯丙胺诱导的神经变性的神经保护作用的分子基础。简要方法将 60 只成年雄性大鼠随机分为 6 组：第 1 组（接受生理盐水）、第 2 组（接受 10 mg/kg 甲基苯丙胺）和第 3、4、5 和 6 组（接受甲基苯丙胺（10 mg/kg））加二甲双胍（分别为 50、75、100 和 150 mg/kg）]。采用高架十字迷宫（EPM）、旷场测试（OFT）、强迫游泳测试（FST）、悬尾测试（TST）和莫里斯水迷宫（MWM）评估实验动物的焦虑、抑郁和认知水平。还分离了动物海马体，并检测氧化应激和炎症参数以及 cAMP 反应元件结合 (CREB)、脑源性神经营养因子 (BDNF)、蛋白激酶 B (Akt) 和糖原合酶激酶 3 (GSK3) 的总形式和磷酸化形式的表达。 ) 蛋白质通过 ELISA 方法进行评估。结果根据获得的数据，甲基苯丙胺引起实验动物显着的抑郁、焦虑、运动活动障碍和认知障碍。二甲双胍在所有使用剂量中均能减少甲基苯丙胺引起的行为障碍。长期服用甲基苯丙胺还可以增加大鼠体内的丙二醛（MDA）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β），同时导致超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）减少和谷胱甘肽还原酶（GR）活性。 二甲双胍，尤其是高剂量的二甲双胍，可以预防甲基苯丙胺的这些有害作用。在甲基苯丙胺治疗的大鼠中，二甲双胍还可以激活 CREB（两种形式）、BDNF 和 Akt（两种形式）蛋白的表达，并抑制 GSK3（两种形式）蛋白的表达。意义 根据获得的数据，二甲双胍可能通过介导 CREB/BDNF 或 Akt/GSK3 信号通路来保护大脑免受甲基苯丙胺诱导的神经变性。这些数据表明 CREB/BDNF 或 Akt/GSK3 信号通路可能在甲基苯丙胺诱导的二甲双胍神经毒性和/或神经保护作用中发挥关键作用。