| 刘崇,刘亚婷,张壮,等.异钩藤碱减轻帕金森病小鼠多巴胺能神经元损伤的作用机制[J].安徽医药,2025,29(1):23-28. |
| 异钩藤碱减轻帕金森病小鼠多巴胺能神经元损伤的作用机制 |
| Mechanism of action of isorhynchophylline in attenuating dopaminergic neuronal damage in Parkinson's mice |
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| DOI：10.3969/j.issn.1009-6469.2025.01.004 |
| 中文关键词: 钩藤属 帕金森病 异钩藤碱 神经元损伤 转录因子 SP1 亮氨酸重复序列激酶 2 |
| 英文关键词: Uncaria Parkinson disease Isorhynchophylline Neuron damage Transcription factor SP1 Leucine repetitive kinase 2 |
| 基金项目:河南省医学科技攻关计划联合共建项目( LHGJ20191454) |
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| 中文摘要: |
| 目的探讨异钩藤碱对帕金森病( PD)小鼠多巴胺能神经元损伤及凋亡的影响及其可能作用机制。方法 2020年 6月至 2022年 6月选取 40只小鼠建立 PD模型，造模成功小鼠按照随机数字表法分为模型组、异钩藤碱低、中和高剂量组，每组各 10只，另设对照组 10只。异钩藤碱低、中和高剂量组小鼠分别灌胃给药 20、40、80 mg/kg的异钩藤碱混悬液( 0.9%氯化钠溶液配制)对照组及模型组给予等量 0.9%氯化钠溶液。采用爬杆实验和旷场实验评定各组小鼠行为学变化； ELISA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)水平以及脑组织中多巴胺( DA)水平； TUNEL法检测黑质区神经细胞凋亡；逆转录聚合酶链式反应( RT-PCR)法检测黑质区微 RNA-376b-3p(miR-376b-3p)、转录因子 SP1(SP1)和亮氨酸重复序列激酶 2(LRRK2)的 mRNA相对表达量；蛋白质印迹法检测黑质区 SP1、LRRK2、α-突触核蛋白(α-syn)和酪氨酸羟化酶(TH)蛋白表达情况。结果与对照组( 4.58±0.27)μg/L比较，模型组( 1.35±0.13)μg/L小鼠 DA水平显著降低( P<0.05)。与模型组比较，异钩藤碱低剂量组( 1.86±0.17)μg/L、中剂量组( 2.56±0.21)μg/L和高剂量组( 3.40±0.29)μg/L小鼠 DA水平显著升高(均 P<0.05)，且以异钩藤碱高剂量组最佳。与模型组比较，异钩藤碱低、中和高剂量组小鼠爬杆时间、 IL-1β、TNF-α水平、神经细胞凋亡率、 SP1和 LRRK2 mRNA和蛋白表达水平、 α-syn蛋白水平降低，运动总距离、 miR-376b-3p以及 TH蛋白水平升高( P<0.05)，且以异钩藤碱高剂量组效果最佳( P<0.05)。结论异钩藤碱能够在一定程度上改善 PD小鼠运动功能障碍，减轻神经炎症反应，降低神经细胞凋亡率，可能是通过影响 miR-376b-3p/SP1/LRRK2信号系统发挥作用。 |
| 英文摘要: |
| Objective To investigate the effects of isorhynchophylline on dopaminergic neuronal damage and apoptosis in Parkin-son's (PD) mice and its possible mechanism of action. Methods From June 2020 to June 2022, forty micewere selected to establishthe PD model, and the successful mice were assigned into model group, the low, medium and high dose of isorhynchophylline groupswith 10 mice in each group according to the random number table method,and another 10 mice were selected as control group. Themice in the low, medium andhigh dose groups were given 20, 40 and 80 mg/kg of isorhynchophylline suspension (prepared with 0.9%sodium chloride solution) by gavage, while the control and model groups were given equal amounts of 0.9% sodium chloride solution.The behavioral changes of mice in each group were evaluated by pole climbing test and open field test. The levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and dopamine (DA) in brain were detected by ELISA. TUNEL method was used todetect neuronal apoptosis in substantia nigra. The mRNA relative expression levels of miR-376b-3p, transcription factor SP1 (SP1) andleucine repeat sequence kinase 2 (LRRK2) in the substantium nigra region were detected by reverse transcription quantitative poly-merase chain reaction (RT-qPCR). The expressions of SP1, LRRK2, α-synuclein (α-syn) and tyrosine hydroxylase (TH) in substantia nigra were detected by Western blotting. Results Compared with the control group (4.58±0.27) μg/L, the model group (1.35±0.13) μg/L showed a significant decrease in mouse DA levels (P<0.05). Compared with the model group, the low-dose group of isorhynchophyl-line (1.86±0.17) μg/L, the medium-dose group (2.56±0.21) μg/L, and the high-dose group (3.40±0.29) μg/L exhibited significant in-creases in mouse DA levels (all P<0.05), with the high-dose group of isorhynchophylline showing the best effect. Compared with the model group, the climbing time, IL-1β, TNF-α, neuronal apoptosis rate, the expression levels of SP1 and LRRK2 mRNA and protein, α-syn protein expression were decreased, the total distance of exercise, miR-376b-3p, TH protein level were increased of mice in the low, medium and high dose of isorhynchophylline groups (P<0.05), and the high dose of isorhynchophylline was the best (P<0.05). Con. clusion Isorhynchophylline can improve the behavioral dysfunction of PD mice to a certain extent, reduce the neuroinflammatory re-action, and reduce the rate of neuronal apoptosis, which may play a role by affecting miR-376b-3p/SP1/LRRK2 signal system. |
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