Vareniuk I, Pavlov I A, Obrosova I G
Pennington Biomedical Research Center, Louisiana State University System, LA 70808, USA.
Diabetologia. 2008 Nov;51(11):2126-33. doi: 10.1007/s00125-008-1136-3. Epub 2008 Sep 19.
AIMS/HYPOTHESIS: 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 approximately 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.
CONCLUSIONS/INTERPRETATION: 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.
目的/假设:超氧阴离子自由基与一氧化氮反应的产物过氧亚硝酸盐在糖尿病周围神经病变中的重要性证据正在不断涌现。特定一氧化氮合酶同工型在糖尿病相关的亚硝化应激以及神经纤维功能障碍和变性中所起的作用尚不清楚。本研究评估了诱导型一氧化氮合酶(iNOS)对过氧亚硝酸盐损伤周围神经和背根神经节以及糖尿病周围神经病变发展的影响。
用链脲佐菌素使对照小鼠和iNos(也称为Nos2)基因缺陷小鼠(iNos(-/-))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。通过爪退缩、甩尾和热板试验评估热痛觉过敏,通过Randall-Selitto试验评估机械性痛觉过敏,通过von Frey细丝试验评估触觉异常性疼痛。
糖尿病野生型小鼠在周围神经和背根神经节神经元中表现出过氧亚硝酸盐损伤。它们还出现了运动和感觉神经传导速度缺陷、热和机械性痛觉减退、触觉异常性疼痛以及约36%的表皮内神经纤维丧失。糖尿病iNos(-/-)小鼠在周围神经中未表现出硝基酪氨酸和聚(ADP-核糖)积累,但在背根神经节中未免受亚硝化应激。尽管存在后一种情况,但糖尿病iNos(-/-)小鼠保留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比野生型小鼠轻。
结论/解读:iNOS在过氧亚硝酸盐对周围神经的损伤以及糖尿病神经病变的功能和结构变化中起关键作用。轴突和施万细胞而非背根神经节神经元中的亚硝化应激是周围神经功能障碍和变性的基础。