Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities.
Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities.
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DOI：
10.2174/1570159x16666180110130253
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发表时间：
2018
影响因子：
5.3
通讯作者：
Lazarowski A
中科院分区：
文献类型：
--
作者：
Merelli A;Rodríguez JCG;Folch J;Regueiro MR;Camins A;Lazarowski A
神经变性（NDG）与神经功能的进行性丧失以及智力和/或运动障碍有关。影响老年人的几种疾病，包括阿尔茨海默病、肌萎缩性侧索硬化症、亨廷顿病、帕金森病、中风、多发性硬化症和许多其他疾病，是与NDG相关的最相关的疾病。由于其他病理学如难治性癫痫、脑感染或遗传性疾病如“神经变性伴脑铁积累”也会导致慢性脑炎症伴神经细胞丧失，因此NDG可以说影响所有年龄段。由于能量和/或氧供应的不平衡，不同的信号传导机制，包括MAPK/PI 3 K-Akt信号传导通路、突触形成和/或磷脂酰丝氨酸的移位，可能激活所有这些病理学共同的并且也与氧化应激相关的某些中枢执行机制。缺氧诱导因子1-α（HIF-1α）通过基因激活发挥双重作用，在这个意义上，该因子必须“选择”是保护还是杀死受影响的细胞。大多数上述过程都是一个长期的过程，并伴随着大脑中铁的累积。我们假设铁螯合剂的神经保护作用是对抗铁衍生的自由基的产生，并诱导足够的-但不是过度的-HIF-1α激活，因此只有缺氧救援基因将被激活。在这方面，缺氧/炎症神经元中促红细胞生成素受体的表达可能是通过鼻腔施用药理学剂量的Neuro-EPO而起作用的细胞“信号”，不仅诱导神经保护，而且最终诱导神经修复
Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Parkinson's disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as “neurodegeneration with brain iron accumulation”, also lead to chronic brain inflammation with loss of neural cells, NDG can be said to affect all ages. Owing to an energy and/or oxygen supply imbal-ance, different signaling mechanisms including MAPK/PI3K-Akt signaling pathways, glutamatergic synapse formation, and/or translocation of phosphatidylserine, might activate some central executing mechanism common to all these pathologies and also related to oxidative stress. Hypoxia inducible factor 1-α (HIF-1α) plays a twofold role through gene activation, in the sense that this factor has to “choose” whether to protect or to kill the affected cells. Most of the afore-mentioned process-es follow a protracted course and are accompanied by progressive iron accumulation in the brain. We hypothesize that the neuroprotective effects of iron chelators are acting against the generation of free radicals derived from iron, and also induce sufficient -but not excessive- activation of HIF-1α, so that only the hypoxia-rescue genes will be activated. In this regard, the expression of the erythropoietin receptor in hypoxic/inflammatory neurons could be the cellular “sign” to act upon by the na-sal administration of pharmacological doses of Neuro-EPO, inducing not only neuroprotection, but eventually, neurorepair as well