title: Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration.
abstract: 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.
authors: Program in Neuroscience and Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Brian N
authors: BN
authors: Mathur
authors: M Diana
authors: MD
authors: Neely
authors: Melanie
authors: M
authors: Dyllick-Brenzinger
authors: Anurag
authors: A
authors: Tandon
authors: Ariel Y
authors: AY
authors: Deutch
mesh_terms: 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*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D004298:Dopamine
references: J Neurosci. 2003 Oct 1;23(26):8955-66
references: 14523098
references: J Biol Chem. 2005 Aug 5;280(31):28394-401
references: 15919666
references: J Neurochem. 2005 Jun;93(5):1304-13
references: 15934949
references: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3413-8
references: 15716361
references: J Neurochem. 2002 Apr;81(2):301-6
references: 12064477
references: Ann Neurol. 2006 Aug;60(2):260-4
references: 16862585
references: Ann Neurol. 2006 Aug;60(2):158-61
references: 16862578
references: Ann Neurol. 2006 Aug;60(2):243-7
references: 16862580
references: Neurosci Lett. 2005 May 20-27;380(1-2):93-8
references: 15854758
references: Science. 2003 Oct 31;302(5646):819-22
references: 14593166
references: J Neurochem. 2003 Sep;86(5):1297-307
references: 12911637
references: Science. 2003 Oct 31;302(5646):841
references: 14593171
references: Neuroscience. 1992;46(1):49-56
references: 1350665
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73
references: 9600990
references: J Neurosci Methods. 1991 Apr;37(2):173-82
references: 1715499
references: Science. 2000 Nov 3;290(5493):985-9
references: 11062131
references: J Biol Chem. 2004 Mar 12;279(11):10710-9
references: 14672949
references: Ann Neurol. 2006 Aug;60(2):248-52
references: 16862581
references: J Mol Neurosci. 2004;24(3):387-400
references: 15655261
references: Ann Neurol. 2006 Aug;60(2):256-60
references: 16862576
references: Ann Neurol. 2004 Jul;56(1):149-62
references: 15236415
references: Neuron. 2002 Dec 19;36(6):1007-19
references: 12495618
references: J Pharmacol Sci. 2005 Mar;97(3):457-60
references: 15764834
references: Exp Neurol. 2005 Feb;191 Suppl 1:S17-27
references: 15629758
references: Ann Neurol. 2006 Aug;60(2):264-8
references: 16862579
references: Neuron. 2003 Sep 11;39(6):889-909
references: 12971891
references: Ann Neurol. 2006 Aug;60(2):253-5
references: 16862591
references: J Pharmacol Sci. 2005 Feb;97(2):203-11
references: 15684568