GSNO通過穩定HIF-1α促進實驗性TBI(創傷性腦損傷)的功能恢復。(GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α.)


創傷性腦損傷(TBI)由於神經修復機制受損而導致持續性殘疾。TBI和中風後神經修復和功能恢復的關鍵是缺氧誘導因子-1α(HIF-1α)。

基於有關HIF-1α可通過S-亞硝基化穩定的報導,我們測試了S-亞硝基化劑S-亞硝基穀胱甘肽(GSNO)穩定HIF-1α的假設,從而刺激神經修復機制並幫助功能恢復。

TBI由成年大鼠的受控皮質撞擊(CCI)誘導。在CCI後2小時施用GSNO(0.05mg / kg)。每天重複治療直至CCI後第14天。通過運動和認知功能評估了功能恢復,並將恢復與HIF-1α的表現進行了比較。

使用腦內皮細胞測定GSNO介導的HIF-1α的S-亞硝基化的機制。相對來講,未經治療的TBI動物表現出持續的神經行為缺陷,而有經過GSNO治療的TBI改善了神經行為功能。


GSNO還增加了HIF-1α和VEGF的分泌。GSNO對TBI動物神經行為功能的有益作用被通過用HIF-1α抑製劑2-甲氧基雌二醇(2-ME)的治療而隔離。 

GSNO對VEGF的刺激作用不僅被2-ME逆轉,而且還被脫亞硝基化劑二硫蘇糖醇逆轉,證實了我們的假設,即GSNO的益處是通過S-亞硝基化穩定HIF-1α介導的。

使用內皮細胞中的生物素轉換測定法進一步證實了GSNO的HIF-1α的S-亞硝基化。該數據提供證據表明GSNO治療TBI通過S-亞硝基化穩定HIF-1α有助於功能恢復。

GSNO是人腦/身體的天然成分,其外源性給藥對人類沒有顯示出不良影響。
因此,GSNO治療在TBI中的轉化潛力很高。


原文連接


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 (0.05mg/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.

#GSNO #天然誓約
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