Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury.
Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury.
复制标题
缺氧诱导因子-1α稳定化用于创伤性脑损伤的再生治疗。
DOI：
10.4103/1673-5374.206632
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发表时间：
2017-05
影响因子：
6.1
通讯作者：
Singh AK
中科院分区：
文献类型：
--
作者：
Khan M;Khan H;Singh I;Singh AK
轻度创伤性脑损伤（TBI），也称为脑震荡，引发后遗症，导致运动缺陷，认知障碍和微妙的神经行为受损。虽然TBI的急性期与神经炎症和硝基氧化爆发有关，但慢性期显示缺乏对神经修复过程和再生的刺激。一氧化氮（NO）的缺乏，随之而来的干扰NO代谢组，和S-亚硝基化的不平衡机制涉及在阻断神经修复过程和功能恢复的机制，在这两个阶段。缺氧诱导因子-1 α（HIF-1α）是缺氧/缺血的主要调节因子，刺激神经修复过程，从而有助于脑创伤后的功能恢复。NO通过HIF-1α的S-亚硝基化机制调节HIF-1 α的活性。S-亚硝基化受NO代谢物如S-亚硝基谷胱甘肽（GSNO）和过氧亚硝酸盐的动态调节。GSNO稳定HIF-1 α，过氧亚硝酸盐使HIF-1α不稳定。外源性给予GSNO不仅可以稳定HIF-1α和诱导HIF-1α依赖性基因，还可以刺激TBI动物的再生过程并有助于功能恢复。
Mild traumatic brain injury (TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO), the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α), a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.