Parkinson’s disease (PD) is a neurodegenerative disease that affects substantia nigra dopamine neurons. Many studies have documented the role of oxidative stress and angiogenesis in the pathogenesis of PD. Metformin (MTF) is an antidiabetic medication and AMP-activated protein kinase (AMPK) regulator that has shown antioxidant and antiangiogenic properties in many disorders. The aim of this study is to investigate the neuroprotective effect of MTF in a mouse model of rotenone-prompted PD with a highlight on its influence on the AMPK/forkhead box transcription factor O3 (FOXO3) pathway and striatal angiogenesis. In the running study, PD was induced in mice using repeated doses of rotenone and concomitantly treated with MTF 100 or 200 mg/kg/day for 18 days. Rotarod and pole tests were used to examine the animals’ motor functionality. After that, animals were sacrificed, and brains were isolated and processed for immunohistochemical investigations or biochemical analyses. Oxidant stress and angiogenic markers were measured, including reduced glutathione, malondialdehyde, the nuclear factor erythroid 2–related factor 2 (Nrf2), hemoxygenase-1, thioredoxin, AMPK, FOXO3, and vascular endothelial growth factor (VEGF). Results indicated that MTF improved animals’ motor function, improved striatal glutathione, Nrf2, hemoxygenase-1, and thioredoxin. Furthermore, MTF upregulated AMPK-FOXO3 proteins and reduced VEGF and cleaved caspase 3. MTF also increased the number of tyrosine hydroxylase (TH)–stained neurons in the substantia nigra neurons and in striatal neuronal terminals. This study is the first to highlight that the neuroprotective role of MTF is mediated through activation of AMPK-FOXO3 signaling and inhibition of the proangiogenic factor, VEGF. Further studies are warranted to confirm this mechanism in other models of PD and neurodegenerative diseases.

帕金森氏病（PD）是一种神经退行性疾病，会影响黑质多巴胺神经元。许多研究已证明氧化应激和血管生成在PD发病机理中的作用。二甲双胍（MTF）是一种抗糖尿病药物和AMP激活的蛋白激酶（AMPK）调节剂，在许多疾病中均表现出抗氧化和抗血管生成特性。这项研究的目的是研究MTF在鱼藤酮提示的PD小鼠模型中的神经保护作用，并重点介绍其对AMPK /叉头盒转录因子O3（FOXO3）途径和纹状体血管生成的影响。在进行中的研究中，使用重复剂量的鱼藤酮在小鼠中诱发PD，并伴以100或200 mg / kg / day的MTF处理18天。进行了罗塔罗德和极点测试，以检查动物的运动功能。之后，处死动物，分离大脑并进行免疫组织化学研究或生化分析。测量了氧化应激和血管生成标记，包括减少的谷胱甘肽，丙二醛，核因子红系2相关因子2（Nrf2），hemoxygenase-1，硫氧还蛋白，AMPK，FOXO3和血管内皮生长因子（VEGF）。结果表明，MTF改善了动物的运动功能，改善了纹状体谷胱甘肽，Nrf2，hemoxygenase-1和硫氧还蛋白。此外，MTF上调了AMPK-FOXO3蛋白，降低了VEGF并切割了caspase3。MTF还增加了黑质神经元和纹状体神经元末端中酪氨酸羟化酶（TH）染色的神经元的数量。这项研究首次强调了MTF的神经保护作用是通过激活AMPK-FOXO3信号传导和抑制促血管生成因子VEGF介导的。有必要进行进一步的研究以在其他PD和神经退行性疾病模型中确认这种机制。