基于PKA信号通路探讨胆南星对MPTP诱导帕金森病模型小鼠的保护作用-中国药房

基于PKA信号通路探讨胆南星对MPTP诱导帕金森病模型小鼠的保护作用

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篇名：	基于PKA信号通路探讨胆南星对MPTP诱导帕金森病模型小鼠的保护作用
TITLE：	Investigation on the protective effect of Arisaema Cum Bile on MPTP-induced Parkinson’s disease model mice based on PKA signaling pathway
摘要：	目的探讨胆南星对帕金森病（PD）模型小鼠的改善作用及可能机制。方法将60只雄性C57BL/6J小鼠随机分为正常组、模型组、胆南星低剂量组[0.39g/（kg·d）]、胆南星高剂量组[1.56g/（kg·d）]和阳性对照药左旋多巴片组[80mg/（kg·d）]，每组12只。除正常组小鼠注射等体积生理盐水外，其余各组连续5d腹腔注射1-甲基-4-苯基-1，2，3，6-四氢吡啶[MPTP，35mg/（kg·d）]建立亚急性PD模型；造模完成后连续给药治疗7d，于造模前1d、造模第5天和末次给药后进行爬杆实验和线悬挂测试。采用免疫荧光法检测小鼠脑黑质中酪氨酸羟化酶（TH）阳性神经元数量；采用酶联免疫吸附法检测小鼠血清中白细胞介素1β（IL-1β）和肿瘤坏死因子α（TNF-α）水平以及脑黑质中IL-1β、TNF-α、环氧合酶2（COX-2）和诱导型一氧化氮合酶（iNOS）水平；采用Westernblot法检测小鼠脑黑质中cAMP依赖的蛋白激酶催化亚单位α（PKAC-α）、谷胱甘肽过氧化物酶4（GPX4）以及铁蛋白重链多肽1（FTH1）蛋白的表达。结果末次给药后，与正常组比较，模型组小鼠爬杆时间显著延长（P＜0.01），线悬挂评分显著降低（P＜0.01），脑黑质中TH阳性神经元数量显著减少（P＜0.01），血清中IL-1β、TNF-α水平和脑黑质中IL-1β、TNF-α、COX-2、iNOS水平显著升高（P＜0.01），脑黑质中GPX4、PKAC-α和FTH1蛋白表达水平显著降低（P＜0.05或P＜0.01）。与模型组比较，胆南星高剂量组小鼠上述指标水平均显著回调（P＜0.05或P＜0.01）。结论胆南星能够改善MPTP诱导的PD模型小鼠运动能力障碍，减少脑黑质TH神经元死亡，对模型小鼠具有神经保护作用；这可能与其激活PKA信号通路来抑制神经炎症和神经元细胞铁死亡有关。
ABSTRACT：	OBJECTIVE To investigate the improvement effects of Arisaema Cum Bile on Parkinson’s disease （PD） model mice and its potential mechanism. METHODS Sixty male C57BL/6J mice were randomly divided into normal group， model group， Arisaema Cum Bile low-dose group [0.39 g/（kg·d）]， Arisaema Cum Bile high-dose group [1.56 g/（kg·d）] and positive control drug Levodopa tablet group [80 mg/（kg·d）]， with 12 mice in each group. Except that normal group was given constant volume of normal saline， other groups were given 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine [MPTP，35 mg/（kg·d）] intraperitoneally for 5 consecutive days to induce subacute PD model； after modeling， they were given relevant medicine continuously for 7 d； rod climbing test and line suspension test were performed 1 d before modeling， on the 5th day of modeling and after the last medication. The number of tyrosine hydroxylase （TH）-positive neurons in the substantia nigra of mice were measured by immunofluorescence； the levels of interleukin 1β （IL-1β） and tumor necrosis factor α（ TNF-α） in serum and the levels of IL- E-mail：qhwang668@sina.com 1β， TNF-α， cyclooxygenase-2 （COX-2） and inducible nitric oxide synthase （iNOS） in the substantia nigra of mice were measured by enzyme-linked immunosorbent assay. The expression levels of cAMP-dependent protein kinase catalytic subunit α （PKA C-α）， glutathione peroxidase 4 （GPX4） and ferritin heavy chain polypeptide 1 （FTH1） proteins in the substantia nigra of mice was measured by Western blot. RESULTS After last medicine， compared with the normal group， mice in the model group had significantly longer pole-climbing time （P＜0.01）， significantly lower line suspension scores （P＜0.01）， significantly fewer TH-positive neurons in the substantia nigra （P＜0.01）， significantly higher serum concentrations of IL-1β and TNF-α and nigrostriatal concentrations of IL-1β， TNF-α， COX-2 and iNOS （P＜0.01）， while lower protein expression levels of GPX4， PKA C-α and FTH1 in the substantia nigra （P＜0.05 or P＜0.01）. Compared with the model group， the above indexes of mice were significantly returned in Arisaema Cum Bile high-dose group （P＜0.05 or P＜ 0.01）. CONCLUSIONS Arisaema Cum Bile can improve motor impairment and reduce apoptosis of nigrostriatal TH neurons in MPTP-induced PD mice， and has neuroprotective effects on model mice； this may be related to its inhibition of neuroinflammation and the inhibition of ferroptosis by up-regulating PKA signaling pathway.
期刊：	2023年第34卷第15期
作者：	陈桂恩；邓雅方；邓婉柔；伍斌玺；彭东辉；曾元宁；王秋红
AUTHORS：	CHEN Guien，DENG Yafang，DENG Wanrou，WU Binxi，PENG Donghui，ZENG Yuanning，WANG Qiuhong
关键字：	胆南星；帕金森病；1-甲基-4-苯基-1，2，3，6-四氢吡啶；cAMP依赖的蛋白激酶信号通路；神经炎症；铁死亡
KEYWORDS：	Arisaema Cum Bile； Parkinson’s disease； 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine； cAMP-dependent
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