Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
Pain. 2011 Jan;152(1):114-122. doi: 10.1016/j.pain.2010.10.005. Epub 2010 Oct 25.
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.
糖尿病性神经病是糖尿病最常见的并发症之一，会导致日常生活中的各种问题。一些研究表明，脊髓内的许多因素都与痛性糖尿病神经病的症状有关，但目前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 Western blot 测定 RhoA 的细胞内定位和 eNOS 的表达。通过尾部闪烁试验评估热痛觉过敏，通过自动 von Frey 细丝试验评估机械性痛觉过敏，用于链脲佐菌素（STZ）诱导的糖尿病小鼠。与非糖尿病对照组相比，STZ 处理的糖尿病小鼠脊髓中的膜结合型 RhoA 增加。用 RhoA 抑制剂外切酶 C3、肉毒梭菌和 ROCK 抑制剂 Y27632 处理可减轻糖尿病小鼠的热痛觉过敏和机械性痛觉过敏。此外，辛伐他汀的每日治疗可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，辛伐他汀治疗可使其恢复正常。这些结果表明，HMG-CoA 还原酶抑制剂通过抑制 RhoA/ROCK 通路增加 NO 生成，对糖尿病小鼠的热痛觉过敏具有抑制作用。这些结果表明，ROCK 抑制剂和 HMG-CoA 抑制剂可能是缓解痛性糖尿病神经病症状的有吸引力的化合物。
