Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicates that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

大脑对能量代谢的特殊要求很高，葡萄糖是唯一的能量来源。在阿尔茨海默氏病，帕金森氏病和其他神经退行性疾病的患者中发现脑能量代谢和葡萄糖摄取的减少，这在神经退行性疾病和能量代谢之间提供了明确的联系。另一方面，包括胶质母细胞瘤在内的癌症已经增加了葡萄糖的摄取，并依赖有氧糖酵解来进行能量代谢。高效氧化磷酸化向低效需氧糖酵解途径（Warburg效应）的转变为生物合成和增殖提供了大分子。当前的研究表明，存在百年历史的亚甲蓝药物可以在复合物I存在的情况下从NADH接收电子并将其捐赠给细胞色素c，提供替代的电子转移途径。亚甲蓝增加氧气消耗，减少糖酵解，并增加葡萄糖摄取体外。亚甲基蓝在急性治疗后可增强大鼠的葡萄糖吸收和局部脑血流量。另外，亚甲基蓝在神经元和星形胶质细胞中提供了针对体外各种损伤以及阿尔茨海默氏病，帕金森氏病和亨廷顿氏病的啮齿动物模型的保护作用。在胶质母细胞瘤细胞中，亚甲基蓝通过增强线粒体氧化磷酸化作用逆转Warburg效应，在s期阻止胶质瘤细胞周期，并抑制胶质瘤细胞增殖。因此，亚甲蓝激活AMP激活的蛋白激酶，抑制下游的乙酰辅酶A羧化酶和细胞周期蛋白依赖性激酶。总而言之，有越来越多的证据提供了概念上的证明，即通过以下途径增强线粒体的氧化磷酸化作用 替代的线粒体电子转移可能提供针对神经退行性疾病的保护作用，并抑制癌症的扩散。