BDNF -JNK通路在脊髓神经炎症反应调控膀胱疼痛综合症中的作用机制

Several study show that central neurogenic inflammation plays an important role in the pathogenesis of bladder pain syndrome (BPS), but its mechanism remains unclear. We have revealed, in our previous research, activated astrocytes regulated BPS via modulating neurogenic inflammation. Meanwhile, our preceding study revealed an increased expression of p-JNK and inflammatory factors in the spinal cord of BPS animal models, and inflammatory factors played a vital role in the production and maintenance of pain. Many researches show that brain derived neurotrophic factor (BDNF) plays an important role in several chronic pain syndromes. Moreover, our preliminary experiments found an over-expression of BDNF in the spinal cord of BPS animal models, and antagonizing its receptor could inhibit astrocyte activation, down-regulate p - JNK levels, reduce inflammatory cytokines secretion and increase the pain threshold. Thus, we hypothesize that BDNF might active the intracellular JNK pathway and cause the inflammatory factors release via binding its receptor on astrocytes, which might involve in the regulation of pain in BPS. This study intends to reveal the role of BDNF in BPS, and further to make clear the mechanism of BDNF how to activate astrocytes and promote the release of inflammatory factor, and further investigate whether BDNF-JNK pathway regulates BPS via modulating spinal neurogenic inflammation. This study will originally reveal a new mechanism of BPS progression and development from the view of neurogenic inflammation inducing central sensitization, which might provide a new target for the treatment of BPS

研究表明中枢神经炎症反应在膀胱疼痛综合症（BPS）发病中起重要作用，但具体机制不明确。我们前期发现BPS模型脊髓活化星形胶质细胞介导神经炎症反应来调控BPS。同时，还发现BPS模型脊髓p-JNK和炎性因子表达增多,后者参与疼痛信号的产生与维持。研究表明脑源性神经营养性因子（BDNF）在多种痛症中起重要作用。我们预实验显示：BPS模型脊髓BDNF表达增多，拮抗其受体可抑制星形胶质细胞活化、下调p-JNK水平、减少炎性因子分泌、提高疼痛阈值。由此，我们提出假设：BDNF通过结合星形胶质细胞上TrkB受体来激活其内JNK通路介导炎性因子释放来调控BPS的假说。我们将进一步明确BDNF在BPS中的作用，以及BDNF激活星形胶质细胞及炎性因子释放的机制，明确BDNF-JNK通路是否介导脊髓神经炎症反应来调控BPS。本课题将从神经炎症介导中枢敏化的角度揭示BPS发病的新机制，为治疗BPS提供新的靶点。

背景：中枢敏化在环磷酰胺（CYP）引起的膀胱炎痛觉过敏中起重要作用。此外，CYP诱发的慢性内脏疼痛与其他神经性疼痛具有类似的的病理生理机制。研究表明脑源性神经营养性因子（BDNF）以及BDNF-TrkB-p38/JNK信号通路在多种痛症中起重要作用，但尚不清楚该信号通路是否可以调控CYP诱导的膀胱炎模型的病理性疼痛。本研究旨在确定在CYP诱导的膀胱炎大鼠模型中BDNF-TrkB-p38/JNK信号通路是否可以调节病理性疼痛。方法：采用CYP全身注射建立大鼠膀胱疼痛综合征（BPS）模型。腹腔注射TrkB受体拮抗剂ANA-12和鞘内注射rBDNF调节BDNF-TrkB-p38/JNK信号通路。使用up-down法用von-Frey丝评估下腹部病理性疼痛。免疫印迹分析和免疫荧光染色用于测量L6-S1脊髓背角（SDH）中BDNF-TrkB信号以及胶质细胞、p-JNK、p-p38、TNF-α和IL-1β的表达。结果：我们在膀胱炎组SDH中观察到BDNF-TrkB信号的上调以及星形胶质细胞和小胶质细胞激活以及p-JNK、p-p38和促炎因子（TNF-α和IL-1β）的过表达。此外，ANA-12的治疗可减轻CYP诱导的膀胱炎的病理性疼痛并抑制星型胶质细胞和小胶质细胞活化，从而导致TNF-α和IL-1β的产生减少。外源性rBDNF可加剧膀胱炎模型病理性疼痛。结论：BDNF-TrkB-p38/JNK信号通路可能促进星型胶质细胞和小胶质细胞的活化，从而参与了CYP诱导的膀胱炎的病理性疼痛的发生发展。我们的研究表明，调节BDNF-TrkB-p38/JNK信号传导可能对治疗BPS的疼痛症状具有治疗价值。