Vareniuk Igor, Pacher Pal, Pavlov Ivan A, Drel Viktor R, Obrosova Irina G
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Int J Mol Med. 2009 May;23(5):571-80. doi: 10.3892/ijmm_00000166.
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.
强效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起重要作用的证据正在逐渐显现。本研究评估了神经元型一氧化氮合酶（nNOS）对糖尿病诱导的周围神经和背根神经节亚硝化应激、周围神经功能障碍和变性的影响。将对照组和nNOS基因敲除小鼠用链脲佐菌素诱导糖尿病，并维持6周。通过硝基酪氨酸和聚（ADP-核糖）免疫反应性评估过氧亚硝酸盐损伤。通过测量坐骨神经运动和后肢趾部感觉神经传导速度、热痛觉过敏、触觉异常性疼痛和表皮内神经纤维密度来评估糖尿病周围神经病变。对照组nNOS基因敲除小鼠表现出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与非糖尿病野生型小鼠相比略低，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基因敲除小鼠的周围神经均表现出亚硝化应激增强。与糖尿病野生型小鼠不同，糖尿病nNOS基因敲除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基因敲除小鼠均出现运动和感觉神经传导速度缺陷以及热痛觉减退，尽管nNOS基因缺陷略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基因敲除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基因敲除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基因缺陷并不能预防神经传导缺陷、感觉神经病变和表皮内神经纤维丢失的发生。
