他替瑞林通过抑制NF-κB磷酸化来减轻神经炎症的机制研究  

Mechanistic study of taltirelin in attenuating neuroinflammation by suppressing NF-κB phosphorylation

作　　者：朱柯东 陈贵勤 张兆辉[1] Zhu Kedong;Chen Guiqin;Zhang Zhaohui(Department of Neurology,Renmin Hospital of Wuhan University,Wuhan 430060)

机构地区：[1]武汉大学人民医院神经内科,430060

出　　处：《卒中与神经疾病》2024年第3期229-235,241,共8页Stroke and Nervous Diseases

基　　金：国家自然科学基金青年项目(81901292);国家自然科学基金面上项目(82071183);国家重点研发计划项目(2021YFC2502100)。

摘　　要：目的探讨他替瑞林(Taltirelin,TAL)对帕金森病大鼠纹状体核因子-κB(Nuclear factor-kappa B,NF-κB)表达与相关神经炎症的调控作用及其机制。方法通过立体定向手术构建偏侧帕金森病(Parkinson’s disease,PD)大鼠模型;采用阿扑吗啡诱导旋转试验、跨步试验、酪氨酸羟化酶(Tyrosine hydroxylase,TH)免疫组化染色等方法评估模型;将成功模型大鼠随机分为TAL组和对照组,分别每日1次给予腹腔注射3 mg/kg的TAL或等剂量生理盐水,连续1周,从对照组未损毁侧[对照-完整(Control-intact,CTR-Int)组]、对照组损毁侧[对照-损毁(Control-lesion,CTR-Les)组]以及TAL组损毁侧(TAL-Les组)的纹状体中提取RNA进行转录组分析,提取蛋白质并通过免疫印迹等技术检测NF-κB p65、磷酸化NF-κB p65以及神经炎症因子白介素-1β(Interleukin-1 beta,IL-1β)、单核细胞趋化蛋白-1(Monocyte chemoattractant protein-1,MCP-1)的表达水平。结果相比于CTR-Int组,CTR-Les组的NF-κB信号通路中有19个基因表达上调,并且磷酸化NF-κB p65,IL-1β,MCP-1表达显著增多;相较于CTR-Les组,TAL-Les组的NF-κB信号通路中有21个基因表达下调,且磷酸化NF-κB p65,IL-1β,MCP-1表达显著减少。结论他替瑞林抑制了偏侧PD模型大鼠脑区NF-κB p65磷酸化与神经炎症的持续激活,这可能是TAL改善PD模型大鼠运动功能但未引起明显异动症等运动并发症的重要原因之一。Objective To investigate the effects of Taltirelin(TAL)on nuclear factor-kappa B(NF-κB)and neuroinflammation.Methods Hemi-PD Rats were established by stereotactic surgery.Behavioral tests including apomorphine-induced rotation and adjusting step test,and tyrosine hydroxylase(TH)immunohistochemical staining were conducted to verify the modeling.Animals were randomly divided into TAL and control groups,receiving daily intraperitoneal injections of 3 mg/kg TAL or an equivalent volume of saline for one week.RNA was extracted from the striatum of the unlesioned control side(CTR-Int group),the lesioned control side(CTR-Les group),and the TAL-treated lesioned side(TAL-Les group)for transcriptomic analysis.Western blotting was performed to assess the expression levels of NF-κB p65,phosphorylated NF-κB p65,the neuroinflammatory cytokine interleukin-1β(IL-1β),and the monocyte chemoattractant protein-1(MCP-1)in both the substantia nigra and striatum of the CTR-Int,CTR-Les,and TAL-Les groups.Results Compared with the CTR-Int group,the CTR-Les group exhibited upregulation of 19 distinct genes associated with the NF-κB signaling pathway,accompanied by significant increases in the expression levels of phosphorylated NF-κB p65,IL-1β,and MCP-1.Conversely,compared with the CTR-Les TAL-Les group was significantly decreased.Conclusion Tatirelin inhibits the phosphorylation of NF-κB p65 in the brain region of Hemi-PD rats and suppresses the continuous activation of neuroinflammation,which may be one of the major reasons for TAL to improve motor function in rats with PD without causing obvious motor complications.

关 键 词：他替瑞林 核因子-ΚB 帕金森病 神经炎症 

分 类 号：R742.5[医药卫生—神经病学与精神病学]