title: Systemic proteasomal inhibitor exposure enhances dopamine turnover and decreases dopamine levels but does not affect MPTP-induced striatal dopamine depletion in mice.
abstract: The validation of an in vivo proteasomal inhibitor (PSI) model to translate ubiquitin-proteasomal-system dysfunction involved in the pathogenesis of Parkinson's disease (PD) into a commonly accepted animal model is ongoing. Here we first report the effects of systemic administration of the proteasomal inhibitor Z-lle-Glu(OtBu)-Ala-Leu-CHO (3 mg/kg, s.c., six times over 2 weeks) alone to extend the rat model to mice. Second we investigate the consequences of PSI pretreatment 42 weeks before an acute treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57bl/6 mice. HPLC postmortem neurochemistry showed a significant increase in dopamine turnover and decrease of striatal dopamine levels, only 14 weeks after PSI treatment, but no enhancement of dopamine turnover or differences in striatal dopamine levels when comparing MPTP with MPTP plus PSI treatment. Behavioral analysis (rotarod, open field activity) did not indicate that PSI affects this type of motor behavior. Systemic PSI administration in mice appears not to be a valid animal model under the experimental conditions used. Potential solutions are discussed.
authors.affiliation: Department of CNS Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hirst
authors.forename: Boris
authors.initials: B
authors.lastname: Ferger
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004151:Dipeptides / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D013997:Time Factors
chemical_list: D004151:Dipeptides; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; C523463:benzyloxycarbonyl-isoleucyl-leucinal; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine