Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat: The role of CREB/BDNF and Akt/GSK3 signaling pathways
Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat: The role of CREB/BDNF and Akt/GSK3 signaling pathways
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DOI：
10.1016/j.neuro.2019.02.004
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发表时间：
2019-05-01
期刊：
影响因子：
3.4
通讯作者：
Sadr, Samira
中科院分区：
文献类型：
--
作者：
Keshavarzi, Saghar;Kermanshahi, Sareh;Sadr, Samira
背景：甲基苯丙胺是一种神经兴奋剂，具有神经退行性作用，作用机制尚不明确。二甲双胍是一种具有神经保护特性的抗糖尿病药物，但其机制尚未完全了解。本研究探讨了二甲双胍对甲基苯丙胺诱导的神经退行性变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：组1（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[分别接受甲基苯丙胺（10 mg/kg）加二甲双胍（50、75、100和150 mg/kg）]。采用高架迷宫、旷场试验（OFT）、强迫游泳试验（FST）、悬尾试验（TST）和Morris水迷宫（MWM）评定实验动物的焦虑、抑郁和认知水平。另外，分离动物的海马，并通过ELISA方法评估氧化应激和炎症参数以及总的和磷酸化形式的cAMP反应元件结合（CREB B）、脑源性神经营养因子（BDNF）、蛋白激酶B（Akt）和糖原合成酶激酶3（GSK 3）蛋白的表达。根据所获得的数据，甲基安非他明在实验动物中造成严重的抑郁、焦虑、运动活动障碍和认知障碍。在所有使用的剂量中，二甲双胍降低了甲基苯丙胺诱导的行为障碍。甲基苯丙胺慢性给药可使大鼠体内丙二醛（MDA）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1 β）含量升高，同时使超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）活性降低。甲基苯丙胺，特别是高剂量的甲基苯丙胺，可以防止甲基苯丙胺的这些恶性影响。二甲双胍可激活甲基苯丙胺处理大鼠CREB（两种形式）、BDNF和Akt（两种形式）蛋白的表达，抑制GSK 3（两种形式）蛋白的表达。意义：根据所获得的数据，二甲双胍可能通过介导CREB/BDNF或Akt/GSK 3信号通路对甲基苯丙胺诱导的神经变性具有保护作用。这些数据表明，CREB/BDNF或Akt/GSK 3信号通路可能在甲基苯丙胺诱导的神经毒性和/或二甲双胍的神经保护作用中起关键作用。
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-alpha) and interleukine-1 beta (IL-1 beta) 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.