title: Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice.
abstract: 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 H(2)O(2)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 H(2)O(2) 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 H(2)O(2) and Fe(2+). 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.
authors: Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors: Masatoshi
authors: M
authors: Inden
authors: Yoshihisa
authors: Y
authors: Kitamura
authors: Aya
authors: A
authors: Tamaki
authors: Takashi
authors: T
authors: Yanagida
authors: Tomonori
authors: T
authors: Shibaike
authors: Atsuko
authors: A
authors: Yamamoto
authors: Kazuyuki
authors: K
authors: Takata
authors: Hiroyuki
authors: H
authors: Yasui
authors: Takahiro
authors: T
authors: Taira
authors: Hiroyoshi
authors: H
authors: Ariga
authors: Takashi
authors: T
authors: Taniguchi
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D052160:Benzothiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077487:Pramipexole; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014475:Uncoupling Agents / Q000633:toxicity; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D012402:Rotenone; D017665:Hydroxyl Radical; D000077487:Pramipexole; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D004298:Dopamine