Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency.
Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency.
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DOI：
10.3892/ijmm_00000166
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发表时间：
2009-05
影响因子：
5.4
通讯作者：
Obrosova IG
中科院分区：
文献类型：
--
作者：
Vareniuk I;Pacher P;Pavlov IA;Drel VR;Obrosova IG
强氧化剂过氧亚硝酸盐在糖尿病周围神经病变和神经性疼痛中的重要作用的证据正在出现。本研究旨在探讨神经型一氧化氮合酶（nNOS）在糖尿病引起的周围神经和背根神经节亚硝化应激以及周围神经功能障碍和变性中的作用。用链脲佐菌素使对照组和nNOS−/−小鼠患糖尿病，并维持6周。过氧亚硝酸盐损伤进行了评估硝基酪氨酸和聚（ADP-核糖）免疫反应。周围糖尿病神经病变通过测量坐骨神经运动和后肢数字感觉神经传导速度、热痛觉、触觉异常性疼痛和表皮内神经纤维密度来评估。对照nNOS−/−小鼠显示正常的运动神经传导速度和热反应潜伏期，而感觉神经传导速度略低于非糖尿病野生型小鼠，触觉反应阈值和表皮内神经纤维密度分别降低了47%和38%。糖尿病野生型和nNOS−/−小鼠的外周神经都表现出增强的亚硝化应激。与糖尿病野生型小鼠相反，糖尿病nNOS−/−小鼠背根神经节中的硝基酪氨酸和聚（ADP-核糖）免疫荧光接近正常。糖尿病野生型和nNOS−/−小鼠都出现了运动和感觉神经传导速度缺陷和热痛觉减退，尽管nNOS基因缺陷轻微降低了这三种疾病的严重程度。与非糖尿病野生型小鼠相比，对照组和糖尿病nNOS−/−小鼠的触觉反应阈值同样降低。与相应的非糖尿病组相比，糖尿病nNOS−/−小鼠的表皮内神经纤维密度降低了27%，与糖尿病野生型小鼠相比，糖尿病nNOS−/−小鼠的表皮内神经纤维密度降低了20%。总之，nNOS是维持正常周围神经功能和小感觉神经纤维支配所必需的。nNOS基因缺陷不能防止神经传导缺陷、感觉神经病和表皮内神经纤维丢失的发展。
Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS−/− mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS−/− mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS−/− mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS−/− mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS−/− mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS−/− mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS−/− mice compared with the corresponding non-diabetic group, and by 20% in diabetic nNOS−/− mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.
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