Leptin‐deficient (ob/ob) mouse‐ a new animal model of peripheral neuropathy of Type 2 diabetes and obesity
Leptin‐deficient (ob/ob) mouse‐ a new animal model of peripheral neuropathy of Type 2 diabetes and obesity
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DOI：
10.1096/fasebj.21.6.a1199-c
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发表时间：
2007-04
期刊：
影响因子：
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通讯作者：
V. Drel;N. Mashtalir;O. Ilnytska;Valeryi V. Lyzogubov;Fei Li;Jeho Shin;I. Obrosova
中科院分区：
文献类型：
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作者：
V. Drel;N. Mashtalir;O. Ilnytska;Valeryi V. Lyzogubov;Fei Li;Jeho Shin;I. Obrosova
尽管在链脲佐菌素糖尿病啮齿动物（1型糖尿病）中广泛探索了周围糖尿病神经病变（PDN），但在2型糖尿病模型中PDN的信息不足。后者代表了临床试验设计的问题，因为绝大多数糖尿病患者患有2型（非胰岛素依赖型）糖尿病。我们在瘦素缺乏（ob/ob）小鼠中表征PDN，所述瘦素缺乏（ob/ob）小鼠是具有轻度高血糖和肥胖的2型糖尿病模型。约11周龄ob/ob小鼠出现运动（MNCV）和感觉神经传导速度（SNCV）缺陷、热痛觉减退、触觉异常性疼痛和约78%的表皮内神经纤维丢失。它们还增加了周围神经中的山梨醇通路活性，并增加了神经、脊髓和背根神经节中的硝基酪氨酸和聚（ADP-核糖）免疫荧光。非达司他（16 mg kg − 1 d −1，从5周龄开始，持续6周）抑制醛糖还原酶可维持正常的MNCV和SNCV，并减轻热痛觉减退和表皮内神经纤维丢失，但不能减轻触觉异常性疼痛。非达司他处理的ob/ob小鼠的神经、脊髓和DRG中的硝基酪氨酸免疫荧光和聚（ADP-核糖）阳性核数与对照组无差异。总之，ob/ob小鼠是一种新的模型，既有大的运动和感觉纤维，也有小的感觉纤维PDN，并对病理治疗有反应。
Whereas peripheral diabetic neuropathy (PDN) has extensively been explored in streptozotocin‐diabetic rodents (Type 1 diabetes), insufficient information is available on PDN in Type 2 diabetic models. The latter represents a problem for clinical trial design, because the vast majority of diabetic patients have Type 2 (non‐insulin‐dependent) diabetes. We characterized PDN in leptin‐deficient (ob/ob) mouse, a model of Type 2 diabetes with mild hyperglycemia and obesity. ~11‐wk old ob/ob mice developed motor (MNCV) and sensory nerve conduction velocity (SNCV) deficits, thermal hypolagesia, tactile allodynia, and ~78% loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in peripheral nerve, and increased nitrotyrosine and poly(ADP‐ribose) immunofluorescence in nerve, spinal cord and dorsal root ganglia. Aldose reductase inhibition with fidarestat (16 mgkg−1d−1, for 6 wks, from 5 wks of age) preserved normal MNCV and SNCV, and alleviated thermal hypoalgesia and intraepidermal nerve fiber loss, but not tactile allodynia. Nitrotyrosine immunofluorescence and the number of poly(ADP‐ribose) positive nuclei in nerve, spinal cord and DRGs of fidarestat‐treated ob/ob mice did not differ from controls. In conclusion, ob/ob mouse is a new model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment.