Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI.
Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI.
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DOI：
10.1016/j.brainres.2015.11.015
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发表时间：
2016-01-01
期刊：
影响因子：
2.9
通讯作者：
Singh AK
中科院分区：
文献类型：
--
作者：
Khan M;Dhammu TS;Matsuda F;Annamalai B;Dhindsa TS;Singh I;Singh AK
创伤性脑损伤（TBI）破坏了基于一氧化氮（NO）的抗炎和抗兴奋性毒性机制。NO被超氧化物消耗形成过氧亚硝酸盐，导致S-亚硝基谷胱甘肽（GSNO）合成和调节神经保护通路的NO生物利用度降低。神经元过氧亚硝酸盐与TBI后神经元损失和功能缺陷有关。使用挫伤小鼠模型的TBI，我们调查机制的GSNO与过氧亚硝酸盐的神经保护和功能恢复的相反作用。在成年雄性小鼠中通过受控皮质撞击（CCI）诱导TBI。CCI后2 h GSNO处理降低了磷酸神经元型一氧化氮合酶（pnNOS）、α II血影蛋白降解产物和3-NT的表达水平，同时也降低了nNOS和钙蛋白酶的活性。用过氧亚硝酸盐清除剂FeTPPS治疗TBI具有与GSNO治疗相似的效果。在为期两周的TBI研究中，GSNO治疗TBI还减少了神经元变性并改善了神经行为功能。在无细胞系统中，SIN-1（过氧亚硝酸盐供体和3-硝基酪氨酸化剂）增加，而GSNO（S-亚硝基化剂）降低钙蛋白酶活性，这些活动被逆转，分别，FeTPPS和氯化汞，半胱氨酸-NO键断裂剂。这些数据表明，过氧亚硝酸盐介导的激活和GSNO介导的抑制有害的nNOS/钙蛋白酶系统在TBI疾病的神经元保护和功能恢复的病理生物学中发挥关键作用。鉴于GSNO在其他疾病中的安全性记录，其在该TBI研究中的神经保护功效和促进功能恢复使低剂量GSNO成为临床前评估的潜在候选者。
Traumatic brain injury (TBI) derails nitric oxide (NO)-based anti-inflammatory and anti-excitotoxicity mechanisms. NO is consumed by superoxide to form peroxynitrite, leading to decreased NO bioavailability for S-nitrosoglutathione (GSNO) synthesis and regulation of neuroprotective pathways. Neuronal peroxynitrite is implicated in neuronal loss and functional deficits following TBI. Using a contusion mouse model of TBI, we investigated mechanisms for the opposed roles of GSNO versus peroxynitrite for neuroprotection and functional recovery. TBI was induced by controlled cortical impact (CCI) in adult male mice. GSNO treatment at 2 h after CCI decreased the expression levels of phospho neuronal nitric oxide synthase (pnNOS), alpha II spectrin degraded products, and 3-NT, while also decreasing the activities of nNOS and calpains. Treatment of TBI with FeTPPS, a peroxynitrite scavenger, had effects similar to GSNO treatment. GSNO treatment of TBI also reduced neuronal degeneration and improved neurobehavioral function in a two-week TBI study. In a cell free system, SIN-1 (a peroxynitrite donor and 3-nitrotyrosinating agent) increased whereas GSNO (an S-nitrosylating agent) decreased calpain activity, and these activities were reversed by, respectively, FeTPPS and mercuric chloride, a cysteine-NO bond cleaving agent. These data indicate that peroxynitrite-mediated activation and GSNO-mediated inhibition of the deleterious nNOS/calpain system play critical roles in the pathobiology of neuronal protection and functional recovery in TBI disease. Given GSNO’s safety record in other diseases, its neuroprotective efficacy and promotion of functional recovery in this TBI study make low-dose GSNO a potential candidate for preclinical evaluation.