Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4‐phenylbutyrate, a chemical chaperone

• Published in: Journal of neurochemistry 2007-06, Vol.101 (6), p.1491-1504
• Main Authors: Inden, Masatoshi, Kitamura, Yoshihisa, Takeuchi, Hiroki, Yanagida, Takashi, Takata, Kazuyuki, Kobayashi, Yuka, Taniguchi, Takashi, Yoshimoto, Kanji, Kaneko, Masahiko, Okuma, Yasunobu, Taira, Takahiro, Ariga, Hiroyoshi, Shimohama, Shun
• Format: Article
• Language: English
• Subjects: 4‐phenylbutyrate; alpha-Synuclein - analysis; Animals; Biochemistry; Biological and medical sciences; C57BL/6 mouse; Cells, Cultured; Corpus Striatum - chemistry; Corpus Striatum - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine - physiology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Humans; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - prevention & control; Neurology; Neurons - metabolism; Neurotransmitters; Oxidative Stress - drug effects; Parkinson's disease; Parkinsonian Disorders - drug therapy; Phenylbutyrates - therapeutic use; Proteins; Rodents; rotenone; Rotenone - toxicity; substantia nigra; Substantia Nigra - chemistry; Substantia Nigra - physiology; Tauopathies - etiology; Toxicity; α‐synuclein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.04440.x

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 α‐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 α‐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.