RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice
RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice
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DOI：
10.1016/j.pain.2010.10.005
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发表时间：
2011-01
期刊：
影响因子：
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通讯作者：
M. Ohsawa;Megumi Aasato;S. Hayashi;J. Kamei
中科院分区：
文献类型：
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作者：
M. Ohsawa;Megumi Aasato;S. Hayashi;J. Kamei
糖尿病神经病变是糖尿病最常见的并发症之一，在日常生活中引起各种问题。多项研究指出，脊髓中的许多因素都与疼痛性糖尿病神经病变的症状有关，但有效的治疗方案却很少。在本研究中，我们试图阐明 RhoA/Rho 激酶 (ROCK) 通路在糖尿病小鼠热痛觉过敏中的作用。通过蛋白质印迹法测量 RhoA 的细胞内定位和 eNOS 的表达。在链脲佐菌素（STZ）诱导的糖尿病小鼠中，通过甩尾试验评估热痛觉过敏，通过自动冯弗雷丝试验评估机械异常性疼痛。与非糖尿病对照组相比，STZ 治疗的糖尿病小鼠的脊髓显示出膜结合的 RhoA 增加。用 RhoA 抑制剂外切酶 C3、肉毒杆菌和 ROCK 抑制剂 Y27632 治疗可减轻糖尿病小鼠的热痛觉过敏和机械异常性疼痛。此外，每天使用辛伐他汀治疗可以减轻糖尿病小鼠的所有这些变化。糖尿病小鼠脊髓中 eNOS 的表达和 NO 代谢物含量降低，并且通过辛伐他汀治疗使这些变化正常化。目前的结果表明，HMG-CoA 还原酶抑制剂对糖尿病小鼠的热痛觉过敏具有抑制作用，这是通过抑制 RhoA/ROCK 途径增加 NO 产生来介导的。这些结果表明，ROCK 抑制剂和 HMG-CoA 抑制剂可能是缓解疼痛性糖尿病神经病症状的有吸引力的化合物。
Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin (STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies.