A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice
A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice
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DOI：
10.1016/j.ejphar.2007.05.055
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发表时间：
2007-08-13
影响因子：
5
通讯作者：
Obrosova, Irina G.
中科院分区：
文献类型：
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作者：
Drel, Viktor R.;Pacher, Pal;Obrosova, Irina G.
虽然自由基和氧化剂在糖尿病周围神经病变中的重要作用是公认的，亚硝化应激，特别是高活性氧化剂过氧亚硝酸盐的贡献，还没有得到适当的探讨。我们以前的研究结果牵连过氧亚硝酸盐在糖尿病相关的运动和感觉神经传导缺陷和周围神经能量缺乏和聚（ADP-核糖）聚合酶激活与I型糖尿病。在这项研究中，亚硝化应激在糖尿病感觉神经病变的作用进行了评估。过氧亚硝酸盐分解催化剂Fe（III）四-2-（N-三乙二醇单甲醚）吡啶基卟啉（FP 15）以5 mg kg（-1）day（-1）（FP 15）的剂量给予对照和链脲佐菌素（STZ）糖尿病小鼠，在最初3周未治疗后持续3周。糖尿病持续6周的小鼠明显出现热痛觉减退（缩爪、甩尾和热板试验）、机械痛觉减退（尾部压力Randall-Sellito试验）、触觉异常性疼痛（柔性von Frey细丝试验），以及类似于38%的表皮内神经纤维损失。坐骨神经、脊髓灰质和背根神经节神经元中的硝基酪氨酸和聚（ADP-核糖）免疫荧光也增加。FP 15治疗与热和机械性痛觉减退的缓解相关。触觉反应阈值倾向于增加响应过氧亚硝酸盐分解催化剂治疗，但仍然保持类似的59%，低于非糖尿病对照组。FP 15处理的糖尿病大鼠表皮内神经纤维密度比未处理的糖尿病大鼠高25%，但两组之间的差异没有达到统计学显著性（p = 0.054）。过氧亚硝基分解催化剂处理的糖尿病小鼠的坐骨神经、脊髓和背根神经节神经元中的硝基酪氨酸和聚（ADP-核糖）免疫荧光显着降低。总之，亚硝化应激在与I型糖尿病相关的感觉神经病变中起重要作用。研究结果为进一步研究过氧亚硝酸盐分解催化剂在长期糖尿病模型中的作用提供了理论基础。(c)2007 Elsevier B. V.保留所有权利。
Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type I diabetes. In this study the role of nitrosative stress in diabetic sensory neuropathy is evaluated. The peroxynitrite decomposition catalyst Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin (FP15) was administered to control and streptozotocin (STZ)-diabetic mice at the dose of 5 mg kg(-1) day(-1) (FP 15), for 3 weeks after initial 3 weeks without treatment. Mice with 6-week duration of diabetes developed clearly manifest thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall-Sellito test), tactile allodynia (flexible von Frey filament test), and similar to 38% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) irmiumofluorescence in the sciatic nerve, grey matter of spinal cord, and dorsal root ganglion neurons. FP 15 treatment was associated with alleviation of thermal and mechanical hypoalgesia. Tactile response threshold tended to increase in response to peroxynitrite decomposition catalyst treatment, but still remained similar to 59% lower compared with non-diabetic controls. Intraepidermal nerve fiber density was 25% higher in FP15-treated than in untreated diabetic rats, but the difference between two groups did not achieve statistical significance (p = 0.054). Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons of peroxynitrite decomposition catalyst-treated diabetic mice were markedly reduced. In conclusion, nitrosative stress plays an important role in sensory neuropathy associated with Type I diabetes. The findings provide rationale for further studies of peroxynitrite decomposition catalysts in a long-term diabetic model. (c) 2007 Elsevier B.V. All rights reserved.