S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats.
S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats.
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DOI：
10.1186/1742-2094-8-78
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发表时间：
2011-07-06
影响因子：
9.3
通讯作者：
Singh I
中科院分区：
文献类型：
--
作者：
Khan M;Sakakima H;Dhammu TS;Shunmugavel A;Im YB;Gilg AG;Singh AK;Singh I
创伤性脑损伤导致内皮和脑实质的原发和继发性损害，统称为神经血管单位。虽然神经元因坏死而迅速死亡，但内皮细胞继发性损伤的恶性循环加剧了脑外伤后神经血管单位的初始损伤。在激活的内皮细胞中，过量的超氧化物与一氧化氮(NO)反应生成过氧亚硝酸根。过氧亚硝酸盐与血脑屏障(BBB)渗漏、代谢功能改变和神经行为障碍有关。S-亚硝基谷胱甘肽(GSNO)是一种基于亚硝酸基的信号分子，据报道，它不仅能降低脑内过氧化亚硝酸盐和氧化代谢产物的水平，而且在脑外伤、中风和脊髓损伤中还能改善神经功能。因此，我们研究了GSNO是否通过降低过氧亚硝酸盐水平和氧化损伤程度来促进神经修复过程。采用控制性皮质撞击(CCI)方法建立成年雄性大鼠脑损伤模型。脑挫伤后2小时灌胃给予GSNO或3-吗啉-西尼明(SIN-1)(50μg/kg体重)。每天重复相同的剂量，直到终点。比较GSNO治疗组(GSNO组)和SIN-1治疗组(SIN-1组)损伤动物的过氧化亚硝酸盐、一氧化氮、谷胱甘肽(GSH)、脂质过氧化、血脑屏障(BBB)渗漏、水肿、炎症、组织结构、轴突/髓鞘完整性和神经营养因子的变化。在短期内(4-48小时)，SIN-1治疗组的脑组织过氧化亚硝酸盐、过氧化脂质/醛、血脑屏障渗漏、炎症和水肿明显增加，而GSNO治疗组则减少。GSNO还能减少脑梗塞，提高NO和GSH水平。在长期治疗(14天)中，GSNO保护轴突完整性，维持髓鞘水平，促进突触可塑性，并增强神经营养因子的表达。我们的发现表明过氧亚硝酸盐参与了脑外伤的病理生物学过程。GSNO治疗创伤性脑损伤不仅能降低过氧亚硝酸根含量，还能保护神经血管单位的完整性，提示GSNO能拮抗过氧亚硝酸根的毒害作用。长期应用同样小剂量的GSNO治疗可促进突触可塑性，增强神经营养因子的表达。这些结果支持GSNO降低脑损伤后氧化代谢产物水平，保护神经血管单位，促进神经修复机制。
Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury. TBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholino-sydnonimine (SIN-1) (50 μg/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors. SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors. Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI.
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DOI：
10.1038/jcbfm.2009.187
发表时间：
2010-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0306706101
发表时间：
2004-03-23
影响因子：
11.1
作者：
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通讯作者：
Feelisch, M
影响因子：
6.1
作者：
Hoffman, Ann N.;Cheng, Jeffrey P.;Kline, Anthony E.
通讯作者：
Kline, Anthony E.
影响因子：
13.6
作者：
Foster MW;Hess DT;Stamler JS
通讯作者：
Stamler JS
影响因子：
8.3
作者：
Gürsoy-Özdemir, Y;Can, A;Dalkara, T
通讯作者：
Dalkara, T