Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes.
Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes.
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DOI：
10.1007/s00125-008-1136-3
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发表时间：
2008-11
期刊：
影响因子：
8.2
通讯作者：
Obrosova, I. G.
中科院分区：
文献类型：
--
作者：
Vareniuk, I.;Pavlov, I. A.;Obrosova, I. G.
关键词：
过氧亚硝酸盐，超氧阴离子自由基与一氧化氮反应的产物，在周围糖尿病神经病变的重要性的证据正在出现。特定的一氧化氮合酶亚型在糖尿病相关的亚硝化应激和神经纤维功能障碍和变性中的作用仍然未知。本研究旨在探讨诱导型一氧化氮合酶（iNOS）在过氧亚硝基阴离子损伤周围神经和背根神经节以及糖尿病周围神经病变发生发展中的作用。用链脲佐菌素使对照小鼠和iNos（也称为Nos 2）基因缺陷（iNos-/-）小鼠患糖尿病，并维持6周。通过硝基酪氨酸和聚（ADP-核糖）积累（免疫组织化学）评估过氧亚硝酸盐损伤。通过缩爪、甩尾和热板试验评价热痛觉，通过Randall-Selitto试验评价机械痛觉，通过von Frey细丝试验评价触觉异常性疼痛。糖尿病野生型小鼠表现出周围神经和背根神经节神经元的过氧亚硝酸盐损伤。他们还出现运动和感觉神经传导速度缺陷、热和机械性痛觉减退、触觉异常性疼痛和~36%的表皮内神经纤维损失。糖尿病iNos−/−小鼠在外周神经中未显示硝基酪氨酸和聚（ADP-核糖）积聚，但在背根神经节中未受到亚硝化应激的保护。尽管有后一种情况，糖尿病iNos−/−小鼠保持了正常的神经传导速度。糖尿病iNos−/−小鼠的小纤维感觉神经病变也不如野生型小鼠严重。iNOS在过氧亚硝基阴离子对周围神经的损伤以及糖尿病神经病变的功能和结构改变中起关键作用。亚硝化应激在轴突和雪旺细胞，而不是背根神经节神经元，是周围神经功能障碍和变性的基础。
Evidence for the importance of peroxynitrite, a product of superoxide anion radical reaction with nitric oxide, in peripheral diabetic neuropathy is emerging. The role of specific nitric oxide synthase isoforms in diabetes-associated nitrosative stress and nerve fibre dysfunction and degeneration remains unknown. This study evaluated the contribution of inducible nitric oxide synthase (iNOS) to peroxynitrite injury to peripheral nerve and dorsal root ganglia and development of peripheral diabetic neuropathy. Control mice and mice with iNos (also known as Nos2) gene deficiency (iNos−/−) were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) accumulation (immunohistochemistry). Thermal algesia was evaluated by paw withdrawal, tail-flick and hot plate tests, mechanical algesia by the Randall–Selitto test, and tactile allodynia by a von Frey filament test. Diabetic wild-type mice displayed peroxynitrite injury in peripheral nerve and dorsal root ganglion neurons. They also developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and ~36% loss of intraepidermal nerve fibres. Diabetic iNos−/− mice did not display nitrotyrosine and poly(ADP-ribose) accumulation in peripheral nerve, but were not protected from nitrosative stress in dorsal root ganglia. Despite this latter circumstance, diabetic iNos−/− mice preserved normal nerve conduction velocities. Small-fibre sensory neuropathy was also less severe in diabetic iNos−/− than in wild-type mice. iNOS plays a key role in peroxynitrite injury to peripheral nerve, and functional and structural changes of diabetic neuropathy. Nitrosative stress in axons and Schwann cells, rather than dorsal root ganglion neurons, underlies peripheral nerve dysfunction and degeneration.
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影响因子：
7.7
作者：
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影响因子：
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