期刊
NEUROCHEMISTRY INTERNATIONAL
卷 55, 期 8, 页码 760-767出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2009.07.009
关键词
Parkinson's disease; Rotenone; Pramipexole; DJ-1; alpha-Synuclein
资金
- Boehringer Ingelheim (Ingelheim, Germany)
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- National Institute of Biomedical Innovation (NIBIO) in Japan
- Grants-in-Aid for Scientific Research [21390014] Funding Source: KAKEN
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 alpha-synuclein immunoreactivity in some surviving DA neurons. Pramipexole inhibited rotenone-induced DA neuronal death and motor deficits, and reduced immunoreactivity for alpha-synuclein. In addition, pramipexole inhibited the in vitro oligomerization of human wild-type alpha-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)-O-center dot) 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)-O-center dot and induction of Bcl-2 protein. (C) 2009 Elsevier Ltd. All rights reserved.
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