CDK5 及其激活因子在糖尿病神经病理性疼痛发生中的作用及其机制研究

Diabetic Neuropathic Pain (DNP) is one of the most common chronic complications of diabetes, and is also a common disease of pain medicine, seriously affecting the patient's health and quality of life. Since the pathogenesis of DNP is still not clear,at present there is still no effective treatment method for DNP．Recent studies have demonstrated that the cyclin dependent kinase 5 (CDK5) and its activation factors may be involved in the modulation of pain. Our previous experiments found that the expression of CDK5 was upregulated in the bilateral spinal dorsal horn of the DNP model rats, and Cdk5 inhibitor Roscovitine reversed the mechanical withdrawal threshold of the DNP model rats by intrathecal injection, indicating that CDK5 might play an important role in the development of DNP. However, there is no direct evidence that CDK5 and its activation factors are involved in the development of DNP.Therefore, this project aims to explore the roles and mechanisms of CDK5 and its activators in the development of DNP, providing new ideas to elucidate the pathogenesis of DNP and find the new therapeutic targets for the treatment of DNP.

糖尿病神经病理性疼痛(Diabetic Neuropathic Pain,DNP)是糖尿病最常见的慢性并发症之一，也是疼痛科的常见病症，严重影响患者的健康和生活质量。由于DNP的发病机制仍不清楚，目前临床上仍无特效治疗DNP的方法。最近有研究表明，细胞周期素依赖性蛋白激酶-5(Cyclin dependent kinase 5,CDK5)及其激活因子与痛觉的产生密切相关，我们的前期研究发现，DNP模型组大鼠的双侧脊髓背角中CDK5表达上调，鞘内注射CDK5 抑制剂Roscovitine 能翻转DNP大鼠的机械撤足阈值，提示CDK5可能与DNP的发生有关，然而至今仍无直接的证据表明CDK5及其激活因子参与DNP的发生。因此，本项目拟探讨CDK5及其激活因子在DNP发生中的作用及其机制，为阐明DNP的发病机制和寻找治疗DNP的新靶点提供新思路。

本项目研究了CDK5及其激活因子P35在糖尿病神经病理性痛（DNP）发生中的作用及其机制。通过高脂高糖饲料喂养8周联合腹腔注射35mg/kg STZ成功诱导糖尿病神经病理性痛（DNP）大鼠模型，运用蛋白免疫印迹、免疫组化和痛行为学测试等方法发现：DNP大鼠模型脊髓背角CDK5及其激活因子P35表达增加,显著性差异可维持8周，CDK5主要定位于脊髓背角神经元和小胶质细胞，在星形胶质细胞中没有表达。鞘内注射CDK5抑制剂Roscovitine可部分逆转DNP大鼠出现的机械痛觉过敏和热痛敏，表明脊髓背角CDK5可能参与了DNP的发生。DNP大鼠脊髓背角的p38MAPK被激活了，p38MAPK在脊髓背角的激活主要在小胶质细胞。鞘内注射CDK5抑制剂Roscovitine能有效抑制p38MAPK在脊髓背角的激活，表明CDK5参与DNP的发生可能是通过激活 p38MAPK实现的。这些发现对阐明DNP的发病机制和寻找治疗DNP的新靶点有重要意义。