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.