尼莫地平和骨化三醇对 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Zebrafish Parkinson's Disease Model 的神经恢复作用。

IF 1.4 4区 医学 Q4 CLINICAL NEUROLOGY
Journal of Korean Neurosurgical Society Pub Date : 2024-09-01 Epub Date: 2023-12-22 DOI:10.3340/jkns.2023.0189
Myung Ji Kim, Su Hee Cho, Yongbo Seo, Sang-Dae Kim, Hae-Chul Park, Bum-Joon Kim
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引用次数: 0

摘要

目的:帕金森病(Parkinson's disease,PD)是最常见的神经退行性疾病之一,其特征是黑质紧密团(substantia nigra pars compacta)中多巴胺能神经元的丧失。治疗帕金森病的目的是通过替代减少的内源性多巴胺来缓解运动症状。目前,还没有治疗帕金森氏症的改变病情药物。在转化研究时代,斑马鱼(Danio rerio)已成为发现和筛选新药的有效工具。众所周知,神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)会导致人类中脑多巴胺能神经元的类似丧失,并出现相应的帕金森症状。L 型钙通道(LTCC)与线粒体氧化应激的产生有关,而线粒体氧化应激是帕金森病发病机制的基础。因此,我们研究了在MPTP诱导的斑马鱼帕金森病模型中抑制LTCC的神经恢复作用,并提出了一种可能改变帕金森病进展的候选药物:所有实验均使用转基因斑马鱼Tg (dat:EGFP)品系,其中绿色荧光蛋白(GFP)表达于多巴胺能神经元。实验组在受精后 1 至 3 天(dpf)暴露于 500µ㏖ MPTP。候选药物候选药物:左旋多巴 1m㏖、硝苯地平 10µ㏖、尼莫地平 3.5µ㏖、二乙基芪醇 0.3µ㏖、木犀草素 100µ㏖、卡西曲醇 0.25µ㏖在受精后 3 至 5 dpf 暴露。运动活动通过自动跟踪进行评估,多巴胺能神经元通过共聚焦显微镜进行活体观察:结果:左旋多巴、尼莫地平、二乙基己烯雌酚和骨化三醇对恢复受 MPTP 损伤的运动行为有显著的积极作用。尼莫地平和骨化三醇对恢复被 MPTP 削弱的多巴胺能神经元有明显的积极作用。通过运动分析和多巴胺能神经元定量,我们确定了尼莫地平和骨化三醇在斑马鱼MPTP诱导的帕金森病模型中的神经恢复作用:本研究确定了尼莫地平和钙三醇在 MPTP 诱导的帕金森病斑马鱼模型中的神经恢复作用。它们恢复了因 MPTP 作用而受损的多巴胺能神经元,并使运动活动恢复正常。LTCC在神经发育和神经退行性疾病中具有潜在的病理作用。斑马鱼非常适合进行高通量药物筛选,因此可能成为一种有用的工具,用于确定治疗帕金森病的疾病调节疗法。为了揭示帕金森氏症的发病机制并开发针对帕金森氏症的疾病调节治疗方法,需要开展进一步的研究,包括建立斑马鱼遗传模型,通过研究多巴胺能神经元中的Ca2+流入和线粒体功能来阐明疾病调节候选药物的作用机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Neuro-Restorative Effect of Nimodipine and Calcitriol in 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Zebrafish Parkinson's Disease Model.

Objective: Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The treatment of PD aims to alleviate motor symptoms by replacing the reduced endogenous dopamine. Currently, there are no disease-modifying agents for the treatment of PD. Zebrafish (Danio rerio) have emerged as an effective tool for new drug discovery and screening in the age of translational research. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain, with corresponding Parkinsonian symptoms. L-type calcium channels (LTCCs) have been implicated in the generation of mitochondrial oxidative stress, which underlies the pathogenesis of PD. Therefore, we investigated the neuro-restorative effect of LTCC inhibition in an MPTP-induced zebrafish PD model and suggested a possible drug candidate that might modify the progression of PD.

Methods: All experiments were conducted using a line of transgenic zebrafish, Tg(dat:EGFP), in which green fluorescent protein (GFP) is expressed in dopaminergic neurons. The experimental groups were exposed to 500 μmol MPTP from 1 to 3 days post fertilization (dpf). The drug candidates : levodopa 1 mmol, nifedipine 10 μmol, nimodipine 3.5 μmol, diethylstilbestrol 0.3 μmol, luteolin 100 μmol, and calcitriol 0.25 μmol were exposed from 3 to 5 dpf. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized in vivo by confocal microscopy.

Results: Levodopa, nimodipine, diethylstilbestrol, and calcitriol had significant positive effects on the restoration of motor behavior, which was damaged by MPTP. Nimodipine and calcitriol have significant positive effects on the restoration of dopaminergic neurons, which were reduced by MPTP. Through locomotor analysis and dopaminergic neuron quantification, we identified the neuro-restorative effects of nimodipine and calcitriol in zebrafish MPTP-induced PD model.

Conclusion: The present study identified the neuro-restorative effects of nimodipine and calcitriol in an MPTP-induced zebrafish model of PD. They restored dopaminergic neurons which were damaged due to the effects of MPTP and normalized the locomotor activity. LTCCs have potential pathological roles in neurodevelopmental and neurodegenerative disorders. Zebrafish are highly amenable to high-throughput drug screening and might, therefore, be a useful tool to work towards the identification of diseasemodifying treatment for PD. Further studies including zebrafish genetic models to elucidate the mechanism of action of the diseasemodifying candidate by investigating Ca2+ influx and mitochondrial function in dopaminergic neurons, are needed to reveal the pathogenesis of PD and develop disease-modifying treatments for PD.

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来源期刊
CiteScore
2.90
自引率
6.20%
发文量
109
审稿时长
3-8 weeks
期刊介绍: The Journal of Korean Neurosurgical Society (J Korean Neurosurg Soc) is the official journal of the Korean Neurosurgical Society, and published bimonthly (1st day of January, March, May, July, September, and November). It launched in October 31, 1972 with Volume 1 and Number 1. J Korean Neurosurg Soc aims to allow neurosurgeons from around the world to enrich their knowledge of patient management, education, and clinical or experimental research, and hence their professionalism. This journal publishes Laboratory Investigations, Clinical Articles, Review Articles, Case Reports, Technical Notes, and Letters to the Editor. Our field of interest involves clinical neurosurgery (cerebrovascular disease, neuro-oncology, skull base neurosurgery, spine, pediatric neurosurgery, functional neurosurgery, epilepsy, neuro-trauma, and peripheral nerve disease) and laboratory work in neuroscience.
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