Combined treatment with GSNO and CAPE accelerates functional recovery via additive antioxidant activities in a mouse model of TBI.
Combined treatment with GSNO and CAPE accelerates functional recovery via additive antioxidant activities in a mouse model of TBI.
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DOI：
10.1002/jnr.24279
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发表时间：
2018-12
影响因子：
4.2
通讯作者：
Singh AK
中科院分区：
文献类型：
--
作者：
Khan M;Shunmugavel A;Dhammu TS;Khan H;Singh I;Singh AK
创伤性脑损伤（TBI）是导致身体残疾和情感脆弱的主要原因。由于其多机制病因学，包括脱轨的线粒体和细胞能量代谢，TBI的治疗缺乏。我们实验室的先前研究表明，内源性一氧化氮（NO）代谢物S-亚硝基谷胱甘肽（GSNO）通过抗炎和抗神经变性机制提供神经保护并改善神经行为功能。为了加快速度，提高恢复的程度，我们研究了GSNO与咖啡酸苯乙酯（CAPE），一种有效的抗氧化剂化合物，结合使用雄性小鼠模型TBI，控制小鼠皮质的影响。与GSNO或CAPE单药治疗相比，联合治疗加速了认知和抑郁样行为的改善。单独地，GSNO和CAPE都改善了线粒体完整性/功能并降低了氧化损伤;然而，联合治疗对Drp 1和MnSOD的影响更大。此外，虽然CAPE单独激活AMPK，但与GSNO组合时这种激活增强。正常动物的CAPE处理也显著增加了pAMPK、pACC（AMPK底物ACC的活化）和pLKB 1（AMPK激酶LKB 1上游的活化）的表达水平，表明CAPE通过LKB 1活化AMPK。这些结果表明，虽然GSNO和CAPE分别提供神经保护和改善功能恢复，但组合治疗通过显著改善线粒体功能和激活AMPK酶而引起更大的恢复。GSNO和CAPE在人类消费中没有任何已知的不良反应;因此，基于组合治疗的多机制方法值得在人类TBI中进行研究。GSNO与CAPE联合治疗TBI比CAPE或GSNO单药治疗更有效。GSNO和CAPE都是天然存在的有效抗氧化剂，它们已用于人类的其他适应症。
Traumatic brain injury (TBI) is the major cause of physical disability and emotional vulnerability. Treatment of TBI is lacking due to its multi-mechanistic etiology, including derailed mitochondrial and cellular energy metabolism. Previous studies from our laboratory show that an endogenous nitric oxide (NO) metabolite S-nitrosoglutathione (GSNO) provides neuroprotection and improves neurobehavioral function via anti-inflammatory and anti- neurodegenerative mechanisms. To accelerate the rate and enhance the degree of recovery, we investigated combining GSNO with caffeic acid phenethyl ester (CAPE), a potent antioxidant compound, using a male mouse model of TBI, controlled cortical impact in mice. The combination therapy accelerated improvement of cognitive and depresssive-like behavior compared with GSNO or CAPE monotherapy. Separately, both GSNO and CAPE improved mitochondrial integrity/function and decreased oxidative damage; however, the combination therapy had greater effects on Drp1 and MnSOD. Additionally, while CAPE alone activated AMPK, this activation was heightened in combination with GSNO. CAPE treatment of normal animals also significantly increased the expression levels of pAMPK, pACC (activation of AMPK substrate ACC) and pLKB1 (activation of upstream to AMPK kinase LKB1), indicating that CAPE activates AMPK via LKB1. These results show that while GSNO and CAPE provide neuroprotection and improve functional recovery separately, the combination treatment invokes greater recovery by significantly improving mitochondrial functions and activating the AMPK enzyme. Both GSNO and CAPE are in human consumption without any known adverse effects; therefore, a combination therapy-based multi-mechanistic approach is worthy of investigation in human TBI. Combining GSNO with CAPE is more effective in TBI than CAPE or GSNO monotherapy. Both GSNO and CAPE are naturally occurring potent antioxidant and they have been used in human for other indications.
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影响因子：
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通讯作者：
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影响因子：
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