Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons

Wen Ji Yuan,Masahiro Kameda,Takamasa Morimoto,Yasuyuki Miyoshi,Toshihiro Matsui,Tanefumi Baba,Takashi Uozumi,Takashi Agari,Tetsuro Shingo,Hanbai Leung,Kenichiro Muraoka,Meng Jing,Isao Date,Feifei Wang,Takao Yasuhara,Naoki Tajiri

doi:10.1186/1471-2202-9-75

Abstract

BackgroundParkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses.ResultsIn vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration.ConclusionEdaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.

Highlights

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems
Parkinson's disease (PD) is a neurodegenerative disorder characterized by slowly progressive degeneration of DA neurons in the substantia nigra pars compacta, with subsequent damage of nerve terminals accompanied by dopamine (DA) depletion in the striatum [1]
Recent study demonstrated that edaravone suppress the production of nitric oxide and reactive oxygen species by activated microglia [15]. In both cerebral ischemia and PD, free radicals might be one of the critical pathogenesis which accelerates progression of disease. These results suggest that edaravone might have neuroprotective effects on 6-OHDA-treated DA neurons and might on slowly degenerated DA neurons in PD patients through anti-oxidative mechanisms

Summary

Introduction

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. 6-hydroxydopamine (6-OHDA) is widely used for experimental models of PD [3] It damages cells with dopaminergic neuronal attribute, including human neuroblastoma SH-SY5Y [4], PC12 cells derived from rat pheochromocytoma [5] and rat ventral mesencephalic neurons [6]. It is a specific neurotoxin for DA neurons in vivo [2,7]. Mitochondrial dysfunction and oxidative stress might play important roles in the pathogenesis of PD [2], indicating that the experimental model using 6-OHDA might have essential mechanisms in common with PD. Anti-oxidant agents, such as catalase, vitamin E, N-acetyl cysteine, ascorbic acid and pyruvate might exert neuroprotection for 6-OHDA-treated DA neurons [9]

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