Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India.
J Alzheimers Dis. 2018;62(1):15-38. doi: 10.3233/JAD-170589.
For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2. On the contrary, hypoxia to the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration.
为了维持细胞内环境平衡和能量代谢，大脑通常需要源源不断的氧气（O2）供应。然而，在 O2 水平受损（缺氧）或血流减少（缺血）的情况下，组织得不到足够的氧气供应，从而导致大脑细胞内环境失衡。众所周知，缺氧对控制参与广泛生物学过程的蛋白质的表达有显著影响，这些过程包括能量代谢、红细胞生成、血管生成、神经发生到线粒体运输和自噬，从而使神经元细胞能够在缺氧环境中存活。相反，大脑缺氧是导致人类发病率和死亡率的主要原因，最终导致认知障碍、肌肉逐渐无力、运动活动丧失、言语缺陷和瘫痪以及其他病理后果。此外，缺氧导致向脑组织输送的 O2 减少，据推测会导致体内和体外模型中的神经退行性变。同样，据报道，慢性缺氧暴露也与血管形成缺陷有关。这种血管异常导致血流改变、营养物质输送减少以及原本受限的浸润物进入，从而限制了大脑的 O2 供应，并导致神经功能障碍。此外，缺氧在介导大脑关键过程中所起的精确机制作用以及触发与神经退行性变相关的病理信号仍然是个谜。因此，本综述阐明了缺氧在调节大脑关键过程中的复杂作用及其在神经元损伤中的严重程度。此外，还探讨了许多药理学方法来补偿缺氧诱导的神经元损伤，这可能被视为缺氧介导的神经退行性变的一种潜在治疗方法。
