Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration.
Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD.
Shin
Masahiro
M
Commissariat à l'Energie Atomique (CEA), Institut d'Imagerie Biomédicale (I(2)BM), Molecular Imaging Research Center (MIRCen), Bat 61, 18 route du Panorama, BP n°6, F-92265 Fontenay-aux-Roses, France.
Jan
Caroline
C
Jacquard
Carine
C
Jarraya
Béchir
B
Callebert
Jacques
J
Launay
Jean-Marie
JM
Hantraye
Philippe
P
Remy
Philippe
P
Palfi
Stéphane
S
Brouillet
Emmanuel
E
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018476:Hypokinesia / Q000139:chemically induced*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects*
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal