Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
Brown University, Providence, Rhode Island.
J Pain. 2019 May;20(5):501-514. doi: 10.1016/j.jpain.2018.10.007. Epub 2018 Nov 8.
Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K-Cl cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy.
紫杉醇诱导背角小胶质细胞激活和促炎介质的产生，这有助于中枢敏化和疼痛行为的发展和维持。MDA7，1-([3-苄基-3-甲基-2,3-二氢-1-苯并呋喃-6-基]羰基)哌啶，是一种新型高选择性大麻素 2 型（CB2）受体激动剂。我们测试了这样一个假设，即 MDA7 激活 CB2 受体可调节小胶质细胞失调，抑制背角小胶质细胞中脑源性神经营养因子（BDNF）的过度表达，并减轻紫杉醇诱导的中枢敏化和疼痛行为。连续 4 天，各组大鼠随机接受生理盐水或 1.0 mg/kg 的紫杉醇每日腹腔注射，总累积剂量为 4 mg/kg。MDA7 15 mg/kg 腹腔注射或载体在 4 天内给予紫杉醇前 15 分钟给予，并继续给予 10 天。进行了行为和分子研究。紫杉醇诱导背角小胶质细胞中 CB2 受体的表达和白细胞介素（IL）-6 的产生。MDA7 减轻了 IL-6 的表达并促进了 IL-10 的表达。紫杉醇诱导小胶质细胞中 IRF8 和嘌呤能受体 P2X4（P2X4）的表观遗传上调，随后增加钙/钙调蛋白依赖性蛋白激酶 II（CaMKIIα）的α同工型、转录因子 p-CREB 和 ΔFosB 的表达，导致小胶质细胞中 BDNF 的过度产生。紫杉醇还上调了谷氨酸受体亚基 GluR1 和 NR2B 的表达，降低了 K-Cl 共转运蛋白的表达，并诱导大鼠机械性痛觉过敏。MDA7 减轻了所有上述分子变化。我们的数据表明，MDA7 减轻了紫杉醇诱导的大鼠分子和行为变化。展望：本研究提供了证据表明，紫杉醇诱导小胶质细胞失调，并在表观遗传水平上上调小胶质细胞中 BDNF 的表达，导致背角神经元敏化和大鼠机械性痛觉过敏。CB2 激动剂 MDA7 缓解了这些病理过程。MDA7 代表了一种治疗化疗诱导性神经病的创新治疗方法。
