GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α.
GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α.
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DOI：
10.1016/j.bbr.2016.10.037
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发表时间：
2018-03-15
影响因子：
2.7
通讯作者：
Singh AK
中科院分区：
文献类型：
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作者：
Khan M;Dhammu TS;Baarine M;Kim J;Paintlia MK;Singh I;Singh AK
创伤性脑损伤（TBI）由于受损的神经修复机制而导致持续残疾。缺氧诱导因子-1 α（HIF-1α）对脑外伤和脑卒中后的神经修复和功能恢复至关重要。基于HIF-1α可以通过S-亚硝基化来稳定的报道，我们测试了S-亚硝基化剂S-亚硝基谷胱甘肽（GSNO）可以稳定HIF-1α，从而刺激神经修复机制并帮助功能恢复的假设。TBI是通过控制皮质撞击（CCI）在成年大鼠中诱导的。CCI后2小时给予GSNO（0.05mg/kg）。每天重复治疗直至CCI后第14天。通过运动和认知功能评估功能恢复，并与HIF-1α表达进行比较。利用脑内皮细胞确定GSNO介导的HIF-1α S-亚硝基化的机制。虽然未治疗的TBI动物表现出持续的神经行为缺陷，但GSNO治疗TBI改善了神经行为功能。GSNO还可增加HIF-1α和VEGF的表达。GSNO对TBI动物神经行为功能的有益作用可通过HIF-1α抑制剂2-甲氧基乙烯（2-ME）治疗来阻断。GSNO对VEGF的刺激作用不仅被2-ME逆转，而且被脱亚硝基化剂二硫苏糖醇逆转，证实了我们的假设，即GSNO的益处是通过S-亚硝基化稳定HIF-1α介导的。在内皮细胞中使用生物素开关测定进一步证实了GSNO对HIF-1α的S-亚硝基化。这些数据提供了证据表明，GSNO治疗TBI通过S-亚硝基化稳定HIF-1α来帮助功能恢复。GSNO是人脑/人体的天然成分，其外源性给药在人体中未显示出不良反应。因此，GSNO治疗TBI的转化潜力很高。
Traumatic brain injury (TBI) causes sustained disability due to compromised neurorepair mechanisms. Crucial to neurorepair and functional recovery following both TBI and stroke is hypoxia-inducible factor-1 alpha (HIF-1α). Based on reports that HIF-1α could be stabilized via S-nitrosylation, we tested the hypothesis that the S-nitrosylating agent S-nitrosoglutathione (GSNO) would stabilize HIF-1α, thereby stimulating neurorepair mechanisms and aiding in functional recovery. TBI was induced by controlled cortical impact (CCI) in adult rats. GSNO (0.05 mg/kg) was administered at two hours after CCI. The treatment was repeated daily until the 14th day after CCI. Functional recovery was assessed by motor and cognitive functions, and the recovery was compared with the expression of HIF-1α. The mechanisms of GSNO-mediated S-nitrosylation of HIF-1α were determined using brain endothelial cells. While non-treated TBI animals showed sustained neurobehavioral deficits, GSNO treatment of TBI improved neurobehavioral functions. GSNO also increased the expression of HIF-1α and VEGF. The beneficial effects of GSNO on neurobehavioral functions in TBI animals were blocked by treatment with the HIF-1α inhibitor 2-methoxyestradiol (2-ME). The stimulatory effect of GSNO on VEGF was reversed not only by 2-ME but also by the denitrosylating agent dithiothreitol, confirming our hypothesis that GSNO's benefits are mediated by the stabilization of HIF-1α via S-nitrosylation. GSNO's S-nitrosylation of HIF-1α was further confirmed using a biotin switch assay in endothelial cells. The data provide evidence that GSNO treatment of TBI aids functional recovery through stabilizing HIF-1α via S-nitrosylation. GSNO is a natural component of the human brain/body, and its exogenous administration has not shown adverse effects in humans. Therefore, the translational potential of GSNO therapy in TBI is high.