S-亚硝基谷胱甘肽可减少创伤性脑损伤后大鼠的氧化损伤，并促进神经修复机制。
S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats.
机构信息
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
出版信息
J Neuroinflammation. 2011 Jul 6;8:78. doi: 10.1186/1742-2094-8-78.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
创伤性脑损伤（TBI）会导致内皮细胞和脑实质的原发性和继发性损伤，统称为神经血管单元。虽然神经元会因坏死而迅速死亡，但内皮细胞的继发性损伤的恶性循环会加剧 TBI 后神经血管单元的初始损伤。在激活的内皮细胞中，过量的超氧化物与一氧化氮（NO）反应形成过氧亚硝酸盐。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损伤有关。S-亚硝基谷胱甘肽（GSNO）是一种基于亚硝基化的信号分子，不仅可以降低脑内过氧亚硝酸盐和氧化代谢物的水平，还可以改善 TBI、中风和脊髓损伤的神经功能。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。
方法
采用皮质撞击（CCI）诱导成年雄性大鼠 TBI。CCI 后两小时给予 GSNO 或 3-吗啉代-sydnonimine（SIN-1）（50μg/kg 体重）口服。每天重复相同剂量，直至终点。GSNO 治疗（GSNO 组）或 SIN-1 治疗（SIN-1 组）的损伤动物与 vehicle 处理的损伤动物（TBI 组）和 vehicle 处理的假手术动物（Sham 组）相比，在过氧亚硝酸盐、NO、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方面。
结果
SIN-1 治疗 TBI 增加，而 GSNO 治疗减少 TBI 后短时间（4-48 小时）的过氧亚硝酸盐、脂质过氧化物/醛、BBB 渗漏、炎症和水肿。GSNO 还降低了脑梗死，并提高了 NO 和 GSH 的水平。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。
结论
我们的研究结果表明过氧亚硝酸盐参与了 TBI 的病理生理学过程。GSNO 治疗 TBI 不仅降低了过氧亚硝酸盐的水平，而且保护了神经血管单元的完整性，表明 GSNO 减轻了过氧亚硝酸盐的有害作用。TBI 用相同的低剂量 GSNO 进行长期治疗可促进突触可塑性并增强神经营养因子的表达。这些结果支持 GSNO 降低氧化代谢物水平，保护神经血管单元，并促进 TBI 中的神经修复机制。
Zotero 插件