Li Lei, Qin Li, Lu Hai-Long, Li Ping-Jing, Song Yuan-Jian, Yang Rong-Li
Department of Geriatrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China; Department of Genetics, Research Center for Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China.
Brain Res. 2017 Feb 15;1657:208-214. doi: 10.1016/j.brainres.2016.12.024. Epub 2016 Dec 27.
The pathogenesis of Alzheimer's disease (AD) is well documented to involve mitochondrial dysfunction which causes subsequent oxidative stress and energy metabolic failure in hippocampus. Methylene blue (MB) has been implicated to be neuroprotective in a variety of neurodegenerative diseases by restoring mitochondrial function. The present work was to examine if MB was able to improve streptozotocin (STZ)-induced Alzheimer's type dementia in a rat model by attenuating mitochondrial dysfunction-derived oxidative stress and ATP synthesis decline. MB was administrated at a dose of 0.5mg/kg/day for consecutive 7days after bilateral STZ intracerebroventricular (ICV) injection (2.5mg/kg). We first demonstrated that MB treatment significantly ameliorated STZ-induced hippocampus-dependent memory loss in passive avoidance test. We also found that MB has the properties to preserve neuron survival and attenuate neuronal degeneration in hippocampus CA1 region after STZ injection. In addition, oxidative stress was subsequently evaluated by measuring the content of lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Importantly, results from our study showed a remarkable suppression of MB treatment on both MDA production and 4-HNE immunoactivity. Finally, energy metabolism in CA1 region was examined by detecting mitochondrial cytochrome c oxidase (CCO) activity and the resultant ATP production. Of significant interest, our result displayed a robust facilitation of MB on CCO activity and the consequent ATP synthesis. The current study indicates that MB may be a promising therapeutic agent targeting oxidative damage and ATP synthesis failure during AD progression.
阿尔茨海默病（AD）的发病机制已被充分证明涉及线粒体功能障碍，这会导致海马体随后出现氧化应激和能量代谢衰竭。亚甲蓝（MB）已被认为通过恢复线粒体功能在多种神经退行性疾病中具有神经保护作用。本研究旨在探讨MB是否能够通过减轻线粒体功能障碍引起的氧化应激和ATP合成下降，改善链脲佐菌素（STZ）诱导的大鼠阿尔茨海默型痴呆。在双侧脑室内（ICV）注射STZ（2.5mg/kg）后，连续7天每天以0.5mg/kg的剂量给予MB。我们首先证明，在被动回避试验中，MB治疗显著改善了STZ诱导的海马体依赖性记忆丧失。我们还发现，MB具有保护神经元存活和减轻STZ注射后海马体CA1区神经元变性的特性。此外，随后通过测量脂质过氧化产物丙二醛（MDA）和4-羟基壬烯醛（4-HNE）的含量来评估氧化应激。重要的是，我们的研究结果显示，MB治疗对MDA生成和4-HNE免疫活性均有显著抑制作用。最后，通过检测线粒体细胞色素c氧化酶（CCO）活性和由此产生的ATP生成，来研究CA1区的能量代谢。令人感兴趣的是，我们的结果显示MB对CCO活性和随后的ATP合成有显著促进作用。目前的研究表明，MB可能是一种有前景的治疗药物，可针对AD进展过程中的氧化损伤和ATP合成衰竭。
