title: Proteasome inhibitor model of Parkinson's disease in mice is confounded by neurotoxicity of the ethanol vehicle.
abstract: Defects in the ubiquitin-proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z-lle-Glu(OtBu)-Ala-Leu-al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 mul of 70% ethanol over a 2-week-period. We found significant decreases in nigrostriatal dopamine in PSI-treated mice compared with saline-treated mice. However, we observed similar decreases in the ethanol-treated vehicle control group. Administration of ethanol alone led to significant long-term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Landau
authors.forename: Edouard
authors.initials: E
authors.lastname: Kouassi
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Siegrist-Johnstone
authors.forename: Julie
authors.initials: J
authors.lastname: Desbarats
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage*; D006719:Homovanillic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D015102:3,4-Dihydroxyphenylacetic Acid; D000431:Ethanol; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid