TNF-α调控MG介导腰椎间盘突出症根性神经痛的机制

Radicular pain induced by lumbar disc herniation (LDH) is an important clinical trouble. Recently, we found the methylglyoxal (MG) level of plasma was dramatically increased in the LDH radicular pain patients and which was positive related to leg pain; MG participated in LDH-induced mechanical allodynia through MG-derived AGEs/RAGE/STAT3 pathway. But the underlying mechanism up-regulating MG remains unclear. Studies indicated that：as the key enzyme for detoxifying MG, the activity of GLO1 was decreased by the down-regulated protein expression or post-translational modifications; TNF-α could significantly phosphorylate and activate CaMKⅡ. We also found that: the TNF-α levels of plasma were increased in the LDH radicular pain patients and which was positive related to the level of MG; the activity of GLO1 significantly decreased in dorsal root ganglion of LDH rats. These data indicated that CaMKⅡ/GLO1 pathway may play a role in TNF-α-mediated MG up-regulation. In this project, we will explore: 1) the relationship of TNF-α and MG in radicular pain; 2) the decreased activity of GLO1 induced by the down-regulated protein expression or post-translational modifications; 3) the mechanisms of TNF-α-mediated MG up-regulation. The objective of the research will provide new targets for clinical prevention and treatment of LDH-induced radicular pain.

腰椎间盘突出症（LDH）根性神经痛是亟待解决的临床难题。我们前期研究发现：LDH根性神经痛患者血中丙酮醛（MG）含量与下肢疼痛程度呈正相关；MG通过MG-derived AGEs/RAGE/STAT3信号通路介导LDH大鼠痛觉过敏。然而MG上调的机制不清。文献显示：TNF-α可使CaMKⅡ自身磷酸化激活；作为MG代谢限速酶，GLO1可通过蛋白表达下调或翻译后磷酸化修饰降低酶活性。我们也发现：LDH根性神经痛患者血中TNF-α含量明显升高，且与MG呈正相关；LDH大鼠背根神经节中GLO1酶活性明显降低。提示TNF-α可能通过CaMKⅡ/GLO1信号通路上调MG，介导LDH根性神经痛。本课题将：1）明确TNF-α与MG之间的调控关系；2）探讨GLO1通过蛋白表达下调或者翻译后磷酸化修饰介导酶活性降低；3）探讨TNF-α上调MG的分子机制，为临床防治LDH根性神经痛提供新靶点。

绝大部分的腰椎间盘突出症通过严格的保守治疗均能得到治愈，但是腰椎间盘突出症根性神经痛是影响患者坚持保守治疗的重要因素。因此，阐明腰椎间盘突出症根性神经痛的分子机制，为开发有效的靶向药物提供理论基础，具有重大的社会和经济效益。我们既往研究证实背根神经节中MG上调是导致腰椎间盘突出症根性神经痛的主要分子因素。本研究通过检测腰椎间盘突出症根性神经痛病人和模型大鼠背根神经节和突出的髓核组织中MG，证实背根神经节和突出的髓核组织均是MG的主要来源，突出的髓核组织作为免疫原引起无菌性炎症反应，产生TNF-α，腰椎间盘突出症根性神经痛病人突出的髓核中GLO1蛋白表达明显下调，且在模型大鼠及原代培养的髓核细胞中证实TNF-α可引起GLO1酶活性降低，进而导致MG代谢清除降低，异常堆积的MG通过自分泌和旁分泌作用于背根神经节感觉神经元，导致根性神经痛和痛觉过敏。