Division of Spine, Department of Orthopedics, School of Life Science and Technology, Tongji Hospital affiliated to Tongji University, Tongji University, Shanghai, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji University, Ministry of Education, Shanghai, China.
J Cell Physiol. 2020 Sep;235(9):6032-6042. doi: 10.1002/jcp.29530. Epub 2020 Jan 28.
Activation of cannabinoid receptor type II (CB2R) by AM1241 has been demonstrated to protect dopaminergic neurons in Parkinson's disease (PD) animals. However, the specific mechanisms of the action of the CB2R agonist AM1241 for PD treatment have not been characterized. Wild-type (WT), CB1R knockout (CB1-KO), and CB2R knockout (CB2-KO) mice were exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 1 week to obtain a PD mouse model. The therapeutic effects of AM1241 were evaluated in each group. Behavioral tests, analysis of neurotransmitters, and immunofluorescence results demonstrated that AM1241 ameliorated PD in WT animals and CB1-KO animals. However, AM1241 did not ameliorate PD symptoms in CB2-KO mice. RNA-seq analysis identified the lncRNA Xist as an important regulator of the protective actions of AM1241. Specifically, AM1241 allowed WT and CB1-KO animals treated with MPTP to maintain normal expression of Xist, which affected the expression of miR-133b-3p and Pitx3. In vitro, overexpression of Xist or AM1241 protected neuronal cells from death induced by 6-hydroxydopamine and increased Pitx3 expression. The CB2 receptor agonist AM1241 alleviated PD via regulation of the Xist/miR-133b-3p/Pitx3 axis, and revealed a new approach for PD treatment.
大麻素受体 2 型 (CB2R) 的激活已被证明可保护帕金森病 (PD) 动物中的多巴胺能神经元。然而，CB2R 激动剂 AM1241 治疗 PD 的具体作用机制尚未确定。野生型 (WT)、CB1R 敲除 (CB1-KO) 和 CB2R 敲除 (CB2-KO) 小鼠接受 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 处理 1 周以获得 PD 小鼠模型。在每组中评估 AM1241 的治疗效果。行为测试、神经递质分析和免疫荧光结果表明，AM1241 改善了 WT 动物和 CB1-KO 动物的 PD。然而，AM1241 并未改善 CB2-KO 小鼠的 PD 症状。RNA-seq 分析确定长非编码 RNA Xist 是 AM1241 保护作用的重要调节剂。具体而言，AM1241 允许接受 MPTP 处理的 WT 和 CB1-KO 动物维持 Xist 的正常表达，这影响了 miR-133b-3p 和 Pitx3 的表达。在体外，Xist 或 AM1241 的过表达可保护神经元细胞免受 6-羟多巴胺诱导的死亡，并增加 Pitx3 的表达。CB2 受体激动剂 AM1241 通过调节 Xist/miR-133b-3p/Pitx3 轴缓解 PD，为 PD 治疗提供了新方法。
