Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Biomed Pharmacother. 2024 Nov;180:117515. doi: 10.1016/j.biopha.2024.117515. Epub 2024 Oct 2.
Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN.
化疗诱导的周围神经病变（CIPN）是一种用于治疗癌症的重要副作用，具有复杂的病理生理学，其机制尚不清楚。最近的研究强调了神经炎症，它受内源性大麻素系统（ECS）的调节，与神经胶质细胞激活有关，并且与 Toll 样受体 4（TLR4）在 CIPN 中的作用有关。本研究旨在研究脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）抑制剂 JZL195 的作用，并探讨大麻素受体与胶质细胞中 TLR4 的关系。使用顺铂注射的雄性 C57BL/6 小鼠建立 CIPN 动物模型。通过 von Frey 和丙酮试验评估机械和冷感觉过敏。Western blot 分析用于检测背根神经节（DRG）和脊髓中代谢酶、大麻素受体、神经胶质细胞和神经炎症因子的表达。免疫组织化学用于研究大麻素受体和 TLR4 在神经胶质细胞中的共定位。JZL195 通过抑制 FAAH/MAGL、调节 ECS 和神经炎症因子以及抑制神经胶质细胞活性来缓解疼痛。此外，大麻素受体和 TLR4 与脊髓中的星形胶质细胞和小胶质细胞共定位。本研究强调了 JZL195 调节 ECS 的治疗潜力，并表明脊髓神经胶质细胞中大麻素受体和 TLR4 之间存在相关性，为缓解 CIPN 中的疼痛和神经炎症提供了新的见解。
