Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer’s disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.

代谢应激通过改变细胞的氧化还原和能量状态而转导，是包括糖尿病在内的许多疾病的主要元凶。然而，其在神经系统疾病病理学中的作用仍未完全阐明。二甲双胍是一种双胍类化合物，是FDA批准的抗糖尿病药，通常用于治疗2型糖尿病。最近描述的这种药物所具有的广泛作用暗示了在一系列疾病中的潜在治疗益处。当前的研究表明，二甲双胍可以通过逆转脑损伤（代谢功能障碍，神经元营养不良和细胞丢失）的标志而发挥神经保护作用，此外还伴随着某些脑部疾病（如阿尔茨海默氏病（AD）和沮丧。然而，二甲双胍在神经退行性疾病中发挥保护作用的机制尚未完全阐明。这篇综述的目的是重新研究二甲双胍执行其功能的机制，同时重点研究其对代谢紊乱环境中稳态平衡的影响。我们还将强调代谢应激的重要性，它不仅是许多神经系统疾病的一部分，而且是神经损伤的主要驱动力。有趣的是，我们将探讨代谢应激与AD和抑郁症的病理生物学关系。主要代谢途径的紊乱，包括AMPK，胰岛素和葡萄糖转运蛋白，