Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice.
Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice.
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瘦素缺陷 (ob/ob) 小鼠的亚硝化应激和周围糖尿病神经病变。
DOI：
10.1016/j.expneurol.2007.03.019
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发表时间：
2007
影响因子：
5.3
通讯作者：
Obrosova,IrinaG
中科院分区：
文献类型：
--
作者：
Vareniuk,Igor;Pavlov,IvanA;Drel,ViktorR;Lyzogubov,ValeriyV;Ilnytska,Olga;Bell,SethR;Tibrewala,Jyoti;Groves,JohnT;Obrosova,IrinaG
在1型糖尿病动物模型中，亚硝化应激导致神经传导减慢、热痛觉减退和氮能神经受损。活性氮在2型糖尿病相关神经病变中的作用尚不清楚。这项研究评估了亚硝化应激在ob/ob小鼠功能和结构神经病变中的作用，ob/ob小鼠是一种伴有轻度高血糖和肥胖的2型糖尿病模型。将两种结构不同的过氧亚硝酸根分解催化剂Fe(III)四(N-三乙二醇单甲醚)吡啶基卟啉(Fp15)和Fe(III)四偏四苯基卟啉辛磺酸盐(FeTMPS)按5 mg/kg−1day−1(FP 15)和5和10 mg/kg−1day−1(FeTMPS)剂量分别给予对照组和8周龄ob/ob小鼠3周。11周龄ob/ob小鼠出现运动神经传导速度和后肢指端感觉神经传导速度缺陷，热痛觉减退，触觉过敏，表皮内神经纤维显著丢失(∼78%)。它们还增加了坐骨神经、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。两种结构不同的过氧亚硝酸盐分解催化剂的治疗与恢复正常的MNCV和SNCV以及减轻热痛觉减退有关。触觉反应阈值在过氧亚硝酸盐分解催化剂治疗后增加，但仍保持∼--比非糖尿病对照组低2.7%至3.2%。FP15和FeTMPS均不能减轻表皮内神经纤维的丢失。过氧亚硝酸盐分解催化剂处理的ob/ob小鼠坐骨神经、脊髓和背根神经节中的硝基酪氨酸和聚腺苷二磷酸核糖免疫荧光基本正常。总之，在该动物模型中，亚硝化应激在大运动、大感觉和小感觉神经病相关的功能异常中起重要作用，但在小感觉神经纤维变性中不起作用。过氧亚硝酸盐分解催化剂缓解2型糖尿病相关感觉神经功能障碍，可能是通过不涉及阻止变性改变或促进小感觉神经纤维再生的机制(S)。
Nitrosative stress contributes to nerve conduction slowing, thermal hypoalgesia, and impaired nitrergic innervation in animal models of Type 1 diabetes. The role for reactive nitrogen species in Type 2 diabetes-associated neuropathy remains unexplored. This study evaluated the role for nitrosative stress in functional and structural neuropathic changes in ob/ob mice, a model of Type 2 diabetes with mild hyperglycemia and obesity. Two structurally diverse peroxynitrite decomposition catalysts, Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)-pyridyl porphyrin (FP15) and Fe(III) tetra-mesitylporphyrin octasulfonate (FeTMPS), were administered to control and 8-week-old ob/ob mice for 3 weeks at the doses of 5 mg kg−1day−1(FP15) and 5 and 10 mg kg−1day−1(FeTMPS). The 11-week-old ob/ob mice developed motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (∼78%) loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion neurons. Treatment with two structurally diverse peroxynitrite decomposition catalysts was associated with restoration of normal MNCV and SNCV, and alleviation of thermal hypoalgesia. Tactile response thresholds increased in response to peroxynitrite decomposition catalyst treatment, but still remained ∼2.7- to 3.2-fold lower compared with non-diabetic controls. Intraepidermal nerve fiber loss was not alleviated by either FP15 or FeTMPS. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglia of peroxynitrite decomposition catalyst-treated ob/ob mice were essentially normal. In conclusion, nitrosative stress plays an important role in functional abnormalities associated with large motor, large sensory, and small sensory fiber neuropathy, but not in small sensory nerve fiber degeneration, in this animal model. Peroxynitrite decomposition catalysts alleviate Type 2 diabetes-associated sensory nerve dysfunction, likely by mechanism(s) not involving arrest of degenerative changes or enhanced regeneration of small sensory nerve fibers.