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

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

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Abstract

Background: Parkinson'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. Results: In 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. Conclusion: Edaravone 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.

Original languageEnglish
Article number75
JournalBMC Neuroscience
Volume9
DOIs
Publication statusPublished - Aug 1 2008

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Oxidopamine
Dopaminergic Neurons
Neuroprotective Agents
Parkinson Disease
Tyrosine 3-Monooxygenase
Free Radicals
phenylmethylpyrazolone
Anti-Inflammatory Agents
Staining and Labeling
Neurons
In Situ Nick-End Labeling
Neurotoxins
Amphetamine
Mesencephalon
Nervous System Diseases
Brain Ischemia

ASJC Scopus subject areas

  • Medicine(all)
  • Clinical Neurology
  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. / Yuan, Wen Ji; Yasuhara, Takao; Shingo, Tetsuro; Muraoka, Kenichiro; Agari, Takashi; Kameda, Masahiro; Uozumi, Takashi; Tajiri, Naoki; Morimoto, Takamasa; Jing, Meng; Baba, Tanefumi; Wang, Feifei; Leung, Hanbai; Matsui, Toshihiro; Miyoshi, Yasuyuki; Date, Isao.

In: BMC Neuroscience, Vol. 9, 75, 01.08.2008.

Research output: Contribution to journalArticle

Yuan, WJ, Yasuhara, T, Shingo, T, Muraoka, K, Agari, T, Kameda, M, Uozumi, T, Tajiri, N, Morimoto, T, Jing, M, Baba, T, Wang, F, Leung, H, Matsui, T, Miyoshi, Y & Date, I 2008, 'Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons', BMC Neuroscience, vol. 9, 75. https://doi.org/10.1186/1471-2202-9-75
Yuan, Wen Ji ; Yasuhara, Takao ; Shingo, Tetsuro ; Muraoka, Kenichiro ; Agari, Takashi ; Kameda, Masahiro ; Uozumi, Takashi ; Tajiri, Naoki ; Morimoto, Takamasa ; Jing, Meng ; Baba, Tanefumi ; Wang, Feifei ; Leung, Hanbai ; Matsui, Toshihiro ; Miyoshi, Yasuyuki ; Date, Isao. / Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. In: BMC Neuroscience. 2008 ; Vol. 9.
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abstract = "Background: Parkinson'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. Results: In 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. Conclusion: Edaravone 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.",
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AU - Yasuhara, Takao

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AU - Agari, Takashi

AU - Kameda, Masahiro

AU - Uozumi, Takashi

AU - Tajiri, Naoki

AU - Morimoto, Takamasa

AU - Jing, Meng

AU - Baba, Tanefumi

AU - Wang, Feifei

AU - Leung, Hanbai

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AU - Miyoshi, Yasuyuki

AU - Date, Isao

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N2 - Background: Parkinson'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. Results: In 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. Conclusion: Edaravone 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.

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