Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice

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• 作者：Masatoshi Inden ; Yoshihisa Kitamura ; Aya Tamaki ; Takashi Yanagida ; Tomonori Shibaike ; Atsuko Yamamoto ; Kazuyuki Takata ; Hiroyuki Yasui ; Takahiro Taira ; Hiroyoshi Ariga ; Takashi Taniguchi
• 关键词：Parkinson's disease ; Rotenone ; Pramipexole ; DJ-1 ; α ; -Synuclein
• 刊名：Neurochemistry International
• 出版年：2009
• 出版时间：December 2009
• 年：2009
• 卷：55
• 期：8
• 页码：760-767
• 全文大小：3394 K

文摘

Pramipexole, an agonist for dopamine (DA) D2/D3-receptors, has been used to treat both early and advanced Parkinson's disease (PD). In this study, we examined the effect of pramipexole on DA neurons in a PD model of C57BL/6 mice, which were treated with rotenone (30 mg/kg, p.o.) daily for 28 days. Pramipexole (1 mg/kg, i.p.) was injected daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone caused a loss of DA neurons in the substantia nigra pars compacta (SNpc), motor deficits and the up-regulation of α-synuclein immunoreactivity in some surviving DA neurons. Pramipexole inhibited rotenone-induced DA neuronal death and motor deficits, and reduced immunoreactivity for α-synuclein. In addition, pramipexole inhibited the in vitro oligomerization of human wild-type α-synuclein by H₂O₂ plus cytochrome c. To examine the neuroprotective effect of pramipexole against oxidative stress, we used a DJ-1-knockdown SH-SY5Y cell line and electron spin resonance (ESR) spectrometry. Simultaneous treatment with H₂O₂ and pramipexole resulted in the significant protection of DJ-1-knockdown cells against cell death in a concentration-dependent manner. A high concentration of pramipexole directly scavenged hydroxyl radical (OH) generated from H₂O₂ and Fe²⁺. Furthermore, pramipexole increased Bcl-2 immunoreactivity in DA neurons in the SNpc. These results suggest that pramipexole may protect DA neurons against exposure to rotenone by chronic oral administration, and this effect is mediated by multiple functions including scavenging of OH and induction of Bcl-2 protein.