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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