Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Previous studies have demonstrated that chronic systemic exposure of Lewis rats to rotenone produced many features of PD, and cerebral tauopathy was also detected in the case of severe weight loss. The present study was designed to assess the neurotoxicity of rotenone after daily oral administration for 28 days at several doses in C57BL/6 mice. In addition, we examined the protective effects of 4-phenylbutyrate (4-PBA) on nigral dopamine (DA) neurons in rotenone-treated mice. 4-PBA was injected intraperitoneally daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone at high doses induced specific nigrostriatal DA neurodegeneration, motor deficits and the up-regulation of alpha-synuclein in the surviving DA neurons. In contrast to the Lewis rat model, cerebral tauopathy was not detected in this mouse model. 4-PBA inhibited rotenone-induced neuronal death and decreased the protein level of alpha-synuclein. These results suggest that this rotenone mouse model may be useful for understanding the mechanism of DA neurodegeneration in PD, and that 4-PBA has a neuroprotective effect in the treatment of PD.
Inden
Masatoshi
M
Department of Neurobiology and 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto, Japan.
Kitamura
Yoshihisa
Y
Takeuchi
Hiroki
H
Yanagida
Takashi
T
Takata
Kazuyuki
K
Kobayashi
Yuka
Y
Taniguchi
Takashi
T
Yoshimoto
Kanji
K
Kaneko
Masahiko
M
Okuma
Yasunobu
Y
Taira
Takahiro
T
Ariga
Hiroyoshi
H
Shimohama
Shun
S
D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000737:chemistry* / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010654:Phenylbutyrates / Q000627:therapeutic use*; D012402:Rotenone / Q000633:toxicity*; D013378:Substantia Nigra / Q000737:chemistry* / Q000502:physiology; D024801:Tauopathies / Q000209:etiology; D051844:alpha-Synuclein / Q000032:analysis
D010654:Phenylbutyrates; D051844:alpha-Synuclein; D012402:Rotenone; C075773:4-phenylbutyric acid; D004298:Dopamine