title: Proteasome inhibitor does not enhance MPTP neurotoxicity in mice.
abstract: Dysfunction of the proteasome function is known to be a potential mechanism for dopaminergic neuron degeneration. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. PSI was injected into MPTP-treated mice over a period of 2 weeks. Thereafter, we evaluated the effect of PSI 2, 4, and 8 weeks after the cessation of treatment with PSI. In the present study with HPLC analysis, PSI did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Our present study with Western blot analysis also demonstrated that the reduction of tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) protein levels in MPTP-treated mice was more pronounced than that in MPTP + PSI-treated animals. These results suggest that proteasome inhibitor did not enhance MPTP neurotoxicity in mice. Our findings suggest that proteasome inhibition is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
authors.affiliation: Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kadoguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Umeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Araki
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009842:Oligopeptides / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine