Journal of Korean Neurosurgical Society

  • 제67권5호
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  • Pages.510-520
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  • 2024
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  • 2005-3711(pISSN)
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  • 1598-7876(eISSN)
대한신경외과학회 (The Korean Neurosurgical Society)
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Neuro-Restorative Effect of Nimodipine and Calcitriol in 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Zebrafish Parkinson's Disease Model

  • Myung Ji Kim (Department of Neurosurgery, Ansan Hospital, Korea University Medical Center, Korea University College of Medicine) ;
  • Su Hee Cho (Department of Neurosurgery, Ansan Hospital, Korea University Medical Center, Korea University College of Medicine) ;
  • Yongbo Seo (Department of Biomedical Sciences, Korea University College of Medicine) ;
  • Sang-Dae Kim (Department of Neurosurgery, Ansan Hospital, Korea University Medical Center, Korea University College of Medicine) ;
  • Hae-Chul Park (Department of Biomedical Sciences, Korea University College of Medicine) ;
  • Bum-Joon Kim (Department of Neurosurgery, Ansan Hospital, Korea University Medical Center, Korea University College of Medicine)
  • 투고 : 2023.09.02
  • 심사 : 2023.12.16
  • 발행 : 2024.09.01
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초록

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 disease-modifying treatment for PD. Further studies including zebrafish genetic models to elucidate the mechanism of action of the disease-modifying 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.

키워드

과제정보

This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2021R1F1A1046947) and Korea University Ansan Hospital (Grant Number O2207231).

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