Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration.
Proteasomal dysfunction has been suggested to contribute to the degeneration of nigrostriatal dopamine neurons in Parkinson's disease. A recent study reported that systemic treatment of rats with the proteasome inhibitor Z-lle-Glu(OtBu)-Ala-Leu-al (PSI) causes a slowly progressive degeneration of nigrostriatal dopamine neurons, the presence of inclusion bodies in dopamine neurons, and motor impairment. We examined in vitro and in vivo the effects of PSI on nigrostriatal dopamine neurons. Mass spectrometric analysis was employed to verify the authenticity of the PSI compound. PSI was non-specifically toxic to neurons in ventral mesencephalic organotypic slice cultures, indicating that impairment of proteasome function in vitro is toxic. Moreover, systemic administration of PSI transiently decreased brain proteasome activity. Systemic treatment of rats with PSI did not, however, result in any biochemical or anatomical evidence of lesions of nigrostriatal dopamine neurons, nor were any changes in locomotor activity observed. These data suggest that systemic administration of proteasome inhibitors to normal adult rats does not reliably cause an animal model of parkinsonism.
Mathur
Brian N
BN
Program in Neuroscience and Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
Neely
M Diana
MD
Dyllick-Brenzinger
Melanie
M
Tandon
Anurag
A
Deutch
Ariel Y
AY
D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D004298:Dopamine
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