Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, P. R. China.
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, P. R. China.
Am J Chin Med. 2020;48(2):407-428. doi: 10.1142/S0192415X20500214. Epub 2020 Mar 5.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of cisplatin, which is characterized by intolerable paresthesia, burning, and hyperalgesia, and severely impacts the life quality of patients. However, no clearly potent drug has been found for clinical medication due to its undefined mechanism. , a traditional Chinese medicine, has been proven to work well in anti-inflammation, blood circulations improvement, hemostasis, and analgesia. This study was designed to observe the effects of Bunting total alkaloids (CSBTA) on cisplatin-induced neuropathic pain and to explore its potential mechanisms. In this study, the rats received intraperitoneal injection of 2mg/kg cisplatin twice a week for five weeks. Meanwhile, oral administration of low (30mg/kg)-, medium (60mg/kg)- and high (120mg/kg)-dose CSBTA were given daily for five weeks. By using Von-frey hair, heat radiant and C cold acetone, we found that CSBTA could obviously relieve cisplatin-induced mechanical, heat, and cold hyperalgesia. It has been verified that cisplatin-induced peripheral neuropathy is related to intraepidermal nerve fibers loss and activation of inflammation downstream. Our research found that Tumor necrosis factor-alpha (TNF-), Interleukin-1beta (IL-1), and Prostaglandin E2 (PGE2) were significantly increased by 10 intraperitoneal injections of cisplatin, and such pro-inflammation cytokines could be reduced via CSBTA administration. Besides, in the cisplatin model group, the neuronal structures of dorsal root ganglia (DRG) were severely damaged and the loss of intraepidermal nerve fibers occurred; but in the CSBTA administration groups, all above pathological changes were improved. Moreover, CSBTA could normalize the overexpression levels of p-p38 and Transient receptor potential vanilloid receptor (TRPV1) induced by cisplatin in DRG, trigeminal ganglion (TG), spinal cord, and foot of rats. In summary, we considered that CSBTA exerted its therapeutic effects by ameliorating neuronal damages, improving intraepidermal nerve fiber (IENF) loss, and inhibiting inflammation-induced p38 phosphorylation to block TRPV1 activation. These findings were the first to confirm the analgesic effect of CSBTA on CIPN and suggested a novel strategy for treating CIPN in clinic.
化疗引起的周围神经病变（CIPN）是顺铂的常见并发症，其特征为难以忍受的感觉异常、烧灼感和痛觉过敏，严重影响患者的生活质量。然而，由于其发病机制尚未明确，尚未发现明确有效的临床用药。作为一种中药，在抗炎、改善血液循环、止血和镇痛方面已被证明有良好的效果。本研究旨在观察 总碱（CSBTA）对顺铂诱导的神经病理性疼痛的影响，并探讨其潜在机制。在这项研究中，大鼠每周两次腹腔注射 2mg/kg 的顺铂，共五周。同时，每天给予低（30mg/kg）、中（60mg/kg）和高（120mg/kg）剂量的 CSBTA 进行口服治疗，共五周。通过使用 Von-frey 毛发、热辐射和 C 冷丙酮，我们发现 CSBTA 能明显缓解顺铂引起的机械、热和冷痛觉过敏。已经证实，顺铂诱导的周围神经病变与表皮内神经纤维丢失和下游炎症激活有关。我们的研究发现，肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1）和前列腺素 E2（PGE2）在 10 次顺铂腹腔注射后显著增加，而 CSBTA 给药可降低这些促炎细胞因子。此外，在顺铂模型组中，背根神经节（DRG）的神经元结构严重受损，表皮内神经纤维丢失；但在 CSBTA 给药组中，所有上述病理变化均得到改善。此外，CSBTA 可使顺铂诱导的大鼠 DRG、三叉神经节（TG）、脊髓和足部的 p-p38 和瞬时受体电位香草酸受体（TRPV1）过度表达水平正常化。综上所述，我们认为 CSBTA 通过改善神经元损伤、改善表皮内神经纤维（IENF）丢失和抑制炎症诱导的 p38 磷酸化来阻断 TRPV1 激活，从而发挥其治疗作用。这些发现首次证实了 CSBTA 对 CIPN 的镇痛作用，并为临床治疗 CIPN 提供了一种新策略。
