Sarkaki Alireza, Farbood Yaghoob, Badavi Mohammad, Khalaj Leila, Khodagholi Fariba, Ashabi Ghorbangol
Department of Physiology, Faculty of Medicine, Jundishapur University of Medical Sciences, P.O.box: 61357-19754, Ahvaz, Iran.
Metab Brain Dis. 2015 Oct;30(5):1139-50. doi: 10.1007/s11011-015-9677-x. Epub 2015 May 5.
Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway.
中风是全球公共卫生面临的主要威胁之一。二甲双胍是一种抗糖尿病药物，是AMP激活的蛋白激酶（AMPK）的激活剂。二甲双胍通过多种途径在改善神经退行性疾病的行为方面发挥重要作用。在本研究中，我们旨在探讨二甲双胍对全脑缺血时焦虑和自噬途径的可能影响。将大鼠分为七组：假手术组、缺血（I/R）组、二甲双胍组（met）、化合物C组（CC）、CC+缺血组、met+缺血组、met+CC+缺血组。二甲双胍预处理2周，在全脑缺血前半小时给予CC。缺血后评估血糖、体重、感觉运动评分、高架十字迷宫试验和旷场试验。通过蛋白质免疫印迹法和免疫荧光分析法检测大鼠海马中自噬相关因子。根据我们的结果，用二甲双胍预处理大鼠可改善缺血大鼠的感觉运动体征、抗焦虑行为和运动能力。在I/R大鼠中注射CC减弱了二甲双胍的治疗效果。与假手术组相比，缺血大鼠的自噬因子如轻链3B、Atg7、Atg5-12和beclin-1减少（所有蛋白质P < 0.001）。与全脑缺血组相比，二甲双胍预处理大鼠的自噬因子水平升高（所有蛋白质P < 0.001）。这些数据表明，二甲双胍在行为和自噬通量方面的有益作用是通过AMPK介导的。我们的结果表明，二甲双胍治疗可改善I/R后的心理障碍和运动障碍，深入了解AMPK依赖的自噬将促进其作为细胞内途径的一个有前景的靶点的发展。
