草乌甲素通过JAK2/STAT3通路抑制Nav1.6表达减轻奥沙利铂诱发的神经病理性疼痛  

Bulleyaconitine A attenuates oxaliplatin-induced neuropathic pain by down-regulating Nav1.6 expression through JAK2/STAT3 signaling pathway

作　　者：刘高丽[1] 刘静 王江栓[3] 吴松[4] LIU Gao-li;LIU Jing;WANG Jiang-shuan;WU Song(Department of Medical Laboratory Techniques,Luohe Medical College,Luohe 462002,China;ICU of Zhengzhou Central Hospital Affiliated to Zhengzhou University,Zhengzhou 450000,China;Department of Human Anatomy,Luohe Medical College,Luohe 462002,China;Department of Computer Application,Luohe Medical College,Luohe 462002,China)

机构地区：[1]漯河医学高等专科学校医学检验技术教研室,河南漯河462002 [2]郑州大学附属郑州中心医院重症监护室,河南郑州450000 [3]漯河医学高等专科学校人体解剖学教研室,河南漯河462002 [4]漯河医学高等专科学校计算机教研室,河南漯河462002

出　　处：《中国病理生理杂志》2021年第9期1628-1635,共8页Chinese Journal of Pathophysiology

基　　金：漯河市2014年度青年拔尖人才支持项目;漯河医学高等专科学校2019年度创新创业发展能力提升工程科研类项目(No.2020-LYZKYZD009);漯河医学高等专科学校2020年度创新创业发展能力提升工程科研类项目(No.2020-LYZKYYB023)。

摘　　要：目的:探讨草乌甲素(BLA)减轻奥沙利铂(OXA)诱发的神经病理性疼痛(NP)的机制。方法:制备OXA诱发的NP大鼠模型,并分别给予0.04 mg/kg、0.12 mg/kg和0.36 mg/kg剂量的BLA治疗。采用von Frey细丝实验和冷板实验评价疼痛敏感度,采用电生理方法检测神经元兴奋性,Western blot检测Janus激酶2(JAK2)/信号转导和转录激活因子3(STAT3)通路相关蛋白及电压门控性钠通道1.6(Nav1.6)蛋白的水平,RT-qPCR检测Nav1.6的mRNA表达。另外在0.36 mg/kg BLA的基础上腹腔注射JAK2激动剂C-A1,探究BLA调控JAK2/STAT3通路和神经元兴奋性的机制。结果:与对照组比较,OXA组机械痛和冷痛阈值及诱发动作电位的最小刺激电流明显降低,静息膜电位(RMP)、动作电位数量、Nav1.6的mRNA和蛋白表达及p-JAK2和p-STAT3蛋白水平均明显升高(P<0.05)。与OXA组比较,0.04 mg/kg BLA仅可显著提高大鼠的冷痛阈值和诱发动作电位的最小刺激电流(P<0.05),而0.12 mg/kg和0.36 mg/kg BLA均可显著升高大鼠的机械痛、冷痛阈值及诱发动作电位的最小刺激电流,降低RMP、动作电位数量、Nav1.6的mRNA和蛋白表达及p-JAK2和p-STAT3的蛋白水平(P<0.05);与0.36 mg/kg BLA组比较,JAK2激动剂C-A1可显著减弱BLA对OXA诱导的大鼠p-JAK2、p-STAT3和Nav1.6蛋白水平及动作电位数量的作用(P<0.05)。结论:BLA减轻OXA诱导大鼠的神经病理性疼痛症状,可能是通过调节JAK2/STAT3通路,抑制Nav1.6蛋白表达并降低神经元兴奋性来实现的。AIM:To investigate the mechanism of bulleyaconitine A(BLA)on reducing oxaliplatin(OXA)-induced neuropathic pain(NP)in rats.METHODS:A rat model of NP induced by OXA was prepared,and the animals were treated with BLA at 0.04 mg/kg,0.12 mg/kg,and 0.36 mg/kg.von Frey filament experiment and cold plate experiment were used to evaluate pain sensitivity.Electrophysiology method was used to detect neuron excitability.Western blot was used to determine the protein levels of Janus kinase 2(JAK2)/signaling transducer and activator of transcription 3(STAT3)signaling pathway related molecules and voltage-gated sodium channel 1.6(Nav1.6),and RT-qPCR was used to detect mRNA expression of Nav1.6.After those,the JAK2 agonist C-A1 was injected intraperitoneally on the basis of 0.36 mg/kg BLA to explore the mechanism of BLA regulating JAK2/STAT3 pathway and neuronal excitability.RESULTS:Compared with control group,the mechanical paw withdrawal threshold,paw withdrawal lantency to cold stimulation and the minimum current to evoke an action potential in OXA group were significantly reduced,the resting membrane potential(RMP),number of action potentials,Nav1.6 expression at mRNA and protein levels,and the protein levels of p-JAK2 and p-STAT3 were significantly increased(P<0.05).Compared with OXA group,BLA at 0.04 mg/kg only significantly increased paw withdrawal lantency to cold stimulation and the minimum current to evoke an action potential in the rats(P<0.05),while BLA at 0.12 mg/kg and 0.36 mg/kg significantly increased the mechanical paw withdrawal threshold,paw withdrawal lantency to cold stimulation and the minimum current to evoke an action potential in rats,reduced RMP,number of action potentials,mRNA and protein levels of Nav1.6,and the protein levels of p-JAK2 and p-STAT3(P<0.05).Compared with 0.36 mg/kg BLA group,JAK2 activator C-A1 significantly attenuated the reduction effects of BLA on the protein levels of p-JAK2,p-STAT3 and Nav1.6,and number of action potentials in the OXAstimulated rats(P<0.05).CONCLUSION:Bulleyaconi

关 键 词：草乌甲素 奥沙利铂 神经病理性疼痛 电压门控性钠通道1.6 JAK2/STAT3信号通路 

分 类 号：R741.02[医药卫生—神经病学与精神病学] R363.2[医药卫生—临床医学]