螺环哌嗪季铵盐化合物LXM-15抗慢性疼痛作用及机制研究

doi:10.5246/jcps.2019.06.036

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (6): 371-380.DOI: 10.5246/jcps.2019.06.036

• 【研究论文】 • 下一篇

螺环哌嗪季铵盐化合物LXM-15抗慢性疼痛作用及机制研究

李宁^1#, 梁莹莹^1#, 孙崎², 蒋益民³, 李润涛^2*, 叶加^1*

1. 北京大学医学部药学院分子与细胞药理学系, 北京 100191
2. 北京大学医学部药学院化学生物学系, 北京 100191
3. 北京大学医学部药学院医药卫生分析中心, 北京 100191

收稿日期:2019-03-24 修回日期:2019-04-17 出版日期:2019-06-30 发布日期:2019-05-10
通讯作者: Tel.: +86-010-82802653; +86-010-82805954, E-mail: yejia@bjmu.edu.cn; lirt@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81870876, 81470050).

The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats

Ning Li^1#, Yingying Liang^1#, Qi Sun², Yimin Jiang³, Runtao Li^2*, Jia Ye^1*

1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3. Department of Medical and Healthy Analysis Center, Peking University Health Science Center, Beijing 100191, China

Received:2019-03-24 Revised:2019-04-17 Online:2019-06-30 Published:2019-05-10
Contact: Tel.: +86-010-82802653; +86-010-82805954, E-mail: yejia@bjmu.edu.cn; lirt@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81870876, 81470050).

摘要/Abstract

摘要：

本研究旨在研究螺环哌嗪季铵盐化合物LXM-15抗完全弗氏佐剂引起的慢性炎性痛, 及慢性坐骨神经压迫损伤(CCI)引起的慢性神经病理性疼痛的作用及机制。结果表明, 在慢性炎性疼痛模型中, 给予LXM-15后, 小鼠足肿胀、踝肿胀明显减轻; 机械缩足阈值和热痛敏缩足潜伏期明显增加。用外周烟碱受体拮抗剂六烃季铵, 或α7烟碱受体拮抗剂甲基牛扁亭预处理, 可阻断LXM-15的抗慢性痛作用。在慢性神经病理性疼痛模型中, LXM-15能明显缓解CCI大鼠的机械刺激痛和热刺激痛觉过敏。进一步研究显示, LXM-15可明显抑制CCI大鼠背根神经节中JAK2和STAT3蛋白的磷酸化, 以及TNF-α和c-fos mRNA的表达。综上所述, 本研究表明LXM-15可缓解啮齿类动物的慢性炎性疼痛和慢性神经病理性疼痛。其作用机制可能是通过激活外周α7烟碱受体, 进一步抑制JAK2 / STAT3信号通路, 降低TNF-α和c-fos的表达。

关键词: 螺环哌嗪季铵盐化合物LXM-15, 慢性疼痛, α7烟碱受体, JAK2/STAT3信号通路

Abstract:

In the present study, we aimed to evaluate the effect of the spirocyclopiperazinium salt compound LXM-15 on chronic inflammatory pain and chronic neuropathic pain induced by complete Freund’s adjuvant (CFA) or chronic constriction injury (CCI) in mice and rats. The results showed that administration with LXM-15 significantly reduced paw edema and ankle swelling and increased the mechanical withdrawal threshold and paw withdrawal latency after CFA injection in mice. LXM-15 significantly alleviated the mechanical allodynia and thermal hyperalgesia in CCI rats. The effect was abolished by pretreatment with hexamethonium (a peripheral nAChR antagonist) or methyllycaconitine citrate (an α7 nAChR antagonist). Furthermore, LXM-15 significantly inhibited the phosphorylation of JAK2 and STAT3, and suppressed the expressions of TNF-α and c-fos in dorsal root ganglia of CCI rats. Collectively, we reported that LXM-15 relieved chronic inflammatory pain in CFA mice and chronic neuropathic pain in CCI rats. The underlying mechanism might be related to the activation of peripheral α7 nicotinic receptor, further inhibiting JAK2/STAT3 signaling pathway, and eventually suppressing the expressions of TNF-α and c-fos.

Key words: Spirocyclopiperazinium salt compound LXM-15, Chronic pain, α7 nicotinic receptor, JAK2/STAT3 signaling pathway

中图分类号:

R966

Supporting:

李宁, 梁莹莹, 孙崎, 蒋益民, 李润涛, 叶加. 螺环哌嗪季铵盐化合物LXM-15抗慢性疼痛作用及机制研究[J]. 中国药学(英文版), 2019, 28(6): 371-380.

Ning Li, Yingying Liang, Qi Sun, Yimin Jiang, Runtao Li, Jia Ye. The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(6): 371-380.

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螺环哌嗪季铵盐化合物LXM-15抗慢性疼痛作用及机制研究

The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats

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