Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy.
Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy.
复制标题
DOI：
10.1002/dmrr.2549
复制
发表时间：
2014-11
影响因子：
8
通讯作者：
Yorek, Mark A.
中科院分区：
文献类型：
--
作者：
Stavniichuk, Roman;Shevalye, Hanna;Lupachyk, Sergey;Obrosov, Alexander;Groves, John T.;Obrosova, Irina G.;Yorek, Mark A.
过氧亚硝酸盐是超氧化物与一氧化氮反应的产物，引起氧化应激，伴随酶失活、多聚（adp -核糖基化）、线粒体功能障碍、应激信号受损以及蛋白质硝化。在这项研究中，我们试图确定预防蛋白质硝化或增加过氧亚硝酸盐分解对长期未经治疗的糖尿病小鼠糖尿病神经病变的影响。C57Bl6/J雄性对照小鼠和糖尿病小鼠在初始高血糖28周后，用过氧亚硝酸盐分解催化剂Fe（III）四聚酰基卟啉八磺酸酯（FeTMPS, 10 mg/kg/d）或蛋白质硝化抑制剂（−）表儿茶素没食子酸酯（20 mg/kg/d）治疗4周。未经治疗的糖尿病小鼠出现运动和感觉神经传导速度缺陷、热痛觉和机械性痛觉减退、触觉异常性痛和表皮内神经纤维丢失。FeTMPS和表儿茶素没食子酸酯均能部分纠正感觉神经传导减慢和小感觉神经纤维功能障碍，但未减轻高血糖。仅用FeTMPS治疗，运动神经传导缺陷得到纠正，表皮内神经纤维密度增加。总之，过氧亚硝酸盐损伤及其组分蛋白质硝化作用与糖尿病周围神经病变的发生有关。研究结果表明，慢性糖尿病周围神经病变的结构和功能改变都是可以逆转的，并为开发新一代抗氧化剂和过氧亚硝酸盐分解催化剂，治疗糖尿病周围神经病变提供了理论依据。
Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction, impaired stress signaling, as well as protein nitration. In this study we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes. C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/d) or protein nitration inhibitor (−)-epicatechin gallate (20 mg/kg/d) for 4 weeks, after an initial 28 weeks of hyperglycemia. Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia, and loss of intraepidermal nerve fibers. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fiber dysfunction without alleviation of hyperglycemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fiber density were found with FeTMPS treatment only. In conclusion, peroxynitrite injury and its component, protein nitration, are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed, and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts, for treatment of diabetic peripheral neuropathy.
登录
查看更多内容
影响因子：
5
作者：
Drel, Viktor R.;Pacher, Pal;Obrosova, Irina G.
通讯作者：
Obrosova, Irina G.
影响因子：
8.2
作者：
Calcutt, NA;Freshwater, JD;Mizisin, AP
通讯作者：
Mizisin, AP
影响因子：
7.7
作者：
Cheng, C;Zochodne, DW
通讯作者：
Zochodne, DW
影响因子：
16.2
作者：
GREENE, DA;SIMA, AAF;LATTIMER, SA
通讯作者：
LATTIMER, SA
影响因子：
2.9
作者：
Fernyhough, P;Brewster, WJ;Tomlinson, DR
通讯作者：
Tomlinson, DR