title: Different effects of intranigral and intrastriatal administration of the proteasome inhibitor lactacystin on typical neurochemical and histological markers of Parkinson's disease in rats.
abstract: Impairment of the ubiquitin-proteasome system, responsible for clearing of misfolded and unwanted proteins, has been implicated in the loss of nigrostriatal dopaminergic neurons characteristic of Parkinson's disease (PD). Recently, proteasome inhibitors have been used to model parkinsonian-like changes in animals. In the present study, the effects of intrastriatal and intranigral injections of the selective proteasome inhibitor lactacystin on key markers of PD were examined in Wistar rats. Comparisons of these two different routes of lactacystin administration revealed that only a unilateral, intranigral injection of lactacystin at a dose of 0.5, 1, 2.5 and 5 μg/2 μl produced after 7 days distinct decreases in the concentrations of dopamine (DA) and its metabolites (DOPAC, 3-MT, HVA) in the ipsilateral striatum. The used doses of lactacystin (except for 0.5 μg/2 μl) significantly accelerated DA catabolism, i.e. the total, oxidative MAO-dependent and COMT-catalyzed pathways, as assessed by HVA/DA, DOPAC/DA and 3-MT/DA ratios, respectively, in the ipsilateral striatum. Such alterations were not observed in the striatal DA content and catabolism either 7, 14 or 21 days after a unilateral, intrastriatal high-dose lactacystin injection (5 and 10 μg/2 μl). Intranigrally administered lactacystin (1 μg/2 μl) caused a marked decline of tyrosine hydroxylase (TH) and α-synuclein protein levels in that structure. Neither TH nor α-synuclein protein levels in the substantia nigra (SN) were affected by high lactacystin doses injected intrastriatally. Moreover, stereological counting of TH-immunoreactive neurons and autoradiographic analysis of [(3)H]GBR 12,935 binding to dopamine transporter confirmed a loss of nigrostriatal dopaminergic neurons after an intranigral lactacystin (1 and 2.5 μg/2 μl) injection. An appearance of cardinal neurochemical and histological changes of parkinsonian type only after intranigral lactacystin injection indicates that DA cell bodies in the SN, but not DA terminals in the striatum are susceptible to proteasome inhibition.
authors.affiliation: Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna St., PL-31-343 Kraków, Poland. lorenc@if-pan.krakow.pl
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Lorenc-Koci
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lenda
authors.forename: Lucyna
authors.initials: L
authors.lastname: Antkiewicz-Michaluk
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Wardas
authors.forename: Helena
authors.initials: H
authors.lastname: Domin
authors.forename: Maria
authors.initials: M
authors.lastname: Smiałowska
authors.forename: Jolanta
authors.initials: J
authors.lastname: Konieczny
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects*
chemical_list: D061988:Proteasome Inhibitors; C067713:lactacystin; D000111:Acetylcysteine