Trifluoro-Icaritin Ameliorates Neuroinflammation Against Complete Freund's Adjuvant-Induced Microglial Activation by Improving CB2 Receptor-Mediated IL-10/β-endorphin Signaling in the Spinal Cord of Rats.

Guangsen Liu, Dandan Jia, Weiwei Li, Zhihua Huang, Reai Shan, Cheng Huang
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Abstract

The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previously identified that trifluoro-icaritin (ICTF) exhibited a significant therapeutic activity against complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, however, the precise mechanisms remain elusive. Here, the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis were used to determine the pain-related behaviors. The expression and co-localization of pain-related signaling molecules were detected by Western blot and immunofluorescence staining. Our results demonstrated that ICTF (3.0 mg/kg, i.p.) effectively attenuated mechanical allodynia, thermal hyperalgesia and improved motor dysfunction induced by CFA, and the molecular docking displayed that CB2 receptor may be the therapeutic target of ICTF. Furthermore, ICTF not only up-regulated the levels of CB2 receptor, IL-10, β-endorphin and CD206, but also reduced the expression of P2Y12 receptor, NLRP3, ASC, Caspase-1, IL-1β, CD11b, and iNOS in the spinal cord of CFA rats. Additionally, the immunofluorescence staining from the spinal cord showed that ICTF significantly increased the co-expression between the microglial marker Iba-1 and CB2 receptor, IL-10, β-endorphin, respectively, but markedly decreased the co-localization between Iba-1 and P2Y12 receptor. Conversely, intrathecal administration of CB2 receptor antagonist AM630 dramatically reversed the inhibitory effects of ICTF on CFA-induced chronic inflammatory pain, leading to a promotion of pain hypersensitivity, abnormal gait parameters, microglial activation, and up-regulation of P2Y12 receptor and NLRP3 inflammasome, as well as the inhibition of CB2 receptor and IL-10/β-endorphin cascade. Taken together, these findings highlighted that ICTF alleviated CFA-induced neuroinflammation by enhancing CB2 receptor-mediated IL-10/β-endorphin signaling and suppressing microglial activation in the spinal cord, and uncovered that CB2 receptor may be exploited as a novel and promising target for ICTF treatment of chronic inflammatory pain.

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通过改善大鼠脊髓中由 CB2 受体介导的 IL-10/β- 内啡肽信号传导,三氟伊卡立汀可改善神经炎症,对抗完全弗氏佐剂诱导的小胶质细胞激活。
慢性炎症性疼痛的潜在发病机制非常复杂,但相关的治疗方法却仍然缺乏。开发治疗慢性炎症性疼痛的有效候选药物迫在眉睫。此前,我们发现三氟水杨酸(ICTF)对完全弗氏佐剂(CFA)诱导的慢性炎症性疼痛具有显著的治疗活性,但其确切的机制仍难以确定。本文采用爪退缩阈值(PWT)、爪退缩潜伏期(PWL)和CatWalk步态分析来确定疼痛相关行为。通过Western印迹和免疫荧光染色检测了疼痛相关信号分子的表达和共定位。结果表明,ICTF(3.0 mg/kg,i.p.)能有效减轻CFA诱导的机械异感、热痛和运动功能障碍,分子对接显示CB2受体可能是ICTF的治疗靶点。此外,ICTF不仅能上调CB2受体、IL-10、β-内啡肽和CD206的水平,还能降低CFA大鼠脊髓中P2Y12受体、NLRP3、ASC、Caspase-1、IL-1β、CD11b和iNOS的表达。此外,脊髓免疫荧光染色显示,ICTF可显著增加小胶质细胞标记物Iba-1与CB2受体、IL-10、β-内啡肽的共表达,但明显降低Iba-1与P2Y12受体的共定位。相反,鞘内注射CB2受体拮抗剂AM630可显著逆转ICTF对CFA诱导的慢性炎症性疼痛的抑制作用,导致痛觉过敏、步态参数异常、小胶质细胞活化、P2Y12受体和NLRP3炎性体上调以及CB2受体和IL-10/β-内啡肽级联反应的抑制。综上所述,这些研究结果表明,ICTF通过增强CB2受体介导的IL-10/β-内啡肽信号传导和抑制脊髓小胶质细胞活化,缓解了CFA诱导的神经炎症,并揭示了CB2受体可作为ICTF治疗慢性炎症性疼痛的新靶点。
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