Trimethoxyflavanone relieves Paclitaxel-induced neuropathic pain via inhibiting expression and activation of P2X7 and production of CGRP in mice
Trimethoxyflavanone relieves Paclitaxel-induced neuropathic pain via inhibiting expression and activation of P2X7 and production of CGRP in mice
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DOI：
10.1016/j.neuropharm.2023.109584
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发表时间：
2023-05
影响因子：
4.7
通讯作者：
Changqing Mei;Chen-Hao Pan;Linbin Xu;Mengmeng Miao;Qichen Lu;Yang Yu;Pengyu Lin;Wenwei Wu
中科院分区：
文献类型：
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作者：
Changqing Mei;Chen-Hao Pan;Linbin Xu;Mengmeng Miao;Qichen Lu;Yang Yu;Pengyu Lin;Wenwei Wu
紫杉醇（PTX）是一种用于治疗实体瘤的抗癌药物，但其常见的不良反应之一是化疗诱导的周围神经病变（CIPN）。目前，对与CIPN相关的神经性疼痛的了解有限，有效的治疗策略不足。先前的研究报道了柚皮素（一种二氢黄酮化合物）在疼痛中的镇痛作用。在此，我们观察到在PTX诱导的疼痛（PIP）中，柚皮素衍生物三甲氧基黄烷酮（Y3）的抗伤害感受作用上级柚皮素。鞘内注射Y3（1 μg）可逆转PIP的机械阈值和热阈值，并抑制PTX诱导的背根神经节（DRG）神经元的过度兴奋。PTX可增强卫星胶质细胞和背根神经节神经元上亲离子型嘌呤受体P2X7的表达。分子对接模拟预测了Y3和P2X7之间可能的相互作用。Y3降低PTX增强的P2X7在DRG中的表达。电生理记录显示，Y3直接抑制PTX处理的小鼠DRG神经元中P2X7介导的电流，表明Y3抑制PTX给药后DRG中P2X7的表达和功能。Y3还减少了DRG和脊髓背角降钙素基因相关肽（CGRP）的产生。此外，Y3抑制PTX增强的Iba1阳性巨噬细胞样细胞在DRG中的浸润以及脊髓星形胶质细胞和小胶质细胞的过度活化。因此，我们的结果表明，Y3通过抑制P2X7功能、CGRP产生、DRG神经元敏化和异常脊髓胶质细胞活化来减弱PIP。我们的研究表明，Y3可能是一个有前途的候选药物对CIPN相关的疼痛和神经毒性。
Paclitaxel (PTX) is an anticancer drug used to treat solid tumors, but one of its common adverse effects is chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is limited understanding of neuropathic pain associated with CIPN and effective treatment strategies are inadequate. Previous studies report the analgesic actions of Naringenin, a dihydroflavonoid compound, in pain. Here we observed that the anti-nociceptive action of a Naringenin derivative, Trimethoxyflavanone (Y3), was superior to Naringenin in PTX-induced pain (PIP). An intrathecal injection of Y3 (1 μg) reversed the mechanical and thermal thresholds of PIP and suppressed the PTX-induced hyper-excitability of dorsal root ganglion (DRG) neurons. PTX enhanced the expression of ionotropic purinergic receptor P2X7 (P2X7) in satellite glial cells (SGCs) and neurons in DRGs. The molecular docking simulation predicts possible interactions between Y3 and P2X7. Y3 reduced the PTX-enhanced P2X7 expression in DRGs. Electrophysiological recordings revealed that Y3 directly inhibited P2X7-mediated currents in DRG neurons of PTX-treated mice, suggesting that Y3 suppressed both expression and function of P2X7 in DRGs post-PTX administration. Y3 also reduced the production of calcitonin gene-related peptide (CGRP) in DRGs and at the spinal dorsal horn. Additionally, Y3 suppressed the PTX-enhanced infiltration of Iba1-positive macrophage-like cells in DRGs and overactivation of spinal astrocytes and microglia. Therefore, our results indicate that Y3 attenuates PIP via inhibiting P2X7 function, CGRP production, DRG neuron sensitization, and abnormal spinal glial activation. Our study implies that Y3 could be a promising drug candidate against CIPN-associated pain and neurotoxicity.