靶向 CGRP 的单克隆抗体通过减轻神经炎症缓解顺铂诱发的神经性疼痛

IF 2.9 3区 医学 Q2 NEUROSCIENCES Neurotoxicity Research Pub Date : 2024-01-09 DOI:10.1007/s12640-023-00685-w
Shun Xie, Zhenfang Gao, Jiale Zhang, Cong Xing, Yanxin Dong, Lanyin Wang, Zhiding Wang, Yuxiang Li, Ge Li, Gencheng Han, Taiqian Gong
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引用次数: 0

摘要

化疗引起的神经病理性疼痛(CIPN)是抗肿瘤化疗药物的一种常见副作用。它描述了一种与药物累积剂量有关的疼痛病理状态,极大地限制了抗肿瘤治疗的疗效。目前仍缺乏缓解 CIPN 的策略。降钙素基因相关肽(CGRP)是一种参与多种病理性疼痛的神经肽。本研究探讨了CGRP阻断对CIPN的影响及潜在机制。我们使用总剂量为 20.7 毫克/千克的顺铂建立了 CIPN 小鼠模型。用von Frey毛和甩尾试验测量机械和热过敏性。利用 Western 印迹和免疫荧光分别评估了小鼠脊髓中 CGRP 和活化星形胶质细胞的水平。此外,还采用实时定量 PCR(RT-qPCR)技术检测炎症细胞因子(如 IL-6、IL-1β 和 NLRP3)在体外和体内的水平。顺铂治疗后,小鼠脊髓中 CGRP 的表达和星形胶质细胞的激活明显增加。使用靶向 CGRP 的单克隆抗体(ZR8 mAb)进行预处理可有效降低顺铂诱导的机械超敏性和热痛觉敏感性,并减轻神经炎症,这表现在小鼠脊髓和脾脏中 IL-6、IL-1β 和 NLRP3 的表达下调。最后,ZR8 mAb 不会干扰顺铂对肿瘤小鼠的抗肿瘤作用。我们的研究结果表明,用单克隆抗体中和 CGRP 可通过减轻神经炎症有效缓解 CIPN。CGRP是一种很有前景的CIPN治疗靶点。
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Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

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来源期刊
Neurotoxicity Research
Neurotoxicity Research 医学-神经科学
CiteScore
7.70
自引率
5.40%
发文量
164
审稿时长
6-12 weeks
期刊介绍: Neurotoxicity Research is an international, interdisciplinary broad-based journal for reporting both basic and clinical research on classical neurotoxicity effects and mechanisms associated with neurodegeneration, necrosis, neuronal apoptosis, nerve regeneration, neurotrophin mechanisms, and topics related to these themes. Published papers have focused on: NEURODEGENERATION and INJURY Neuropathologies Neuronal apoptosis Neuronal necrosis Neural death processes (anatomical, histochemical, neurochemical) Neurodegenerative Disorders Neural Effects of Substances of Abuse NERVE REGENERATION and RESPONSES TO INJURY Neural Adaptations Neurotrophin mechanisms and actions NEURO(CYTO)TOXICITY PROCESSES and NEUROPROTECTION Excitatory amino acids Neurotoxins, endogenous and synthetic Reactive oxygen (nitrogen) species Neuroprotection by endogenous and exogenous agents Papers on related themes are welcome.
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