Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats

Abstract

Systemic administration of proteasomal inhibitors to rats has been proposed as producing progressive nigral dopaminergic cell loss and impairment of motor function, although this has proved difficult to reproduce. We report reproducible loss of tyrosine hydroxylase-positive cells in substantia nigra and decrease in locomotor activity by proteasomal inhibitor injection in rats up to 10 months after treatment. Dopaminergic cell death was accompanied by the appearance of ubiquitin and alpha-synuclein-positive inclusions in the substantia nigra in these rats. Neuronal loss was also observed in the locus ceruleus, raphe nuclei, and dorsal motor nucleus of the vagus, verifying that proteasomal inhibition produces a relevant model of Parkinson's disease.

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…Matrix located more medially and striosomes have predominant associative-and limbic-related connections, respectively [11]. Similarly to data from previous successful demonstration of systemic proteasome inhibitors' effect on damage of nigrostriatal connections [32,33,38,51], we observed a loss of dopaminergic terminals within the striatum. Previous reports indicated a decrease in dopaminergic innervations of the striatum by 30 to 40%.…”

“…In some experimental conditions, mainly after subcutaneous administration of PSI, a loss of SN dopaminergic neurons was observed and varied between 40% [38] and 50% [51], and even exceeded 50% [33]. Four other groups of researchers, despite the fact that they tried faithfully to follow the experimental protocol proposed by McNaught et al, failed to replicate the results described earlier [6,22,23,30].…”

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

“…Two known genetic causes of PD involve aspects of UPS function (Parkin and UCH-L1), and α-syn is a substrate for the UPS. Reduced UPS activity has been found in brains of sporadic PD patients [48,49] and some investigators have found that administration of UPS inhibitors to rodents can recreate some of the features of PD, although these models remain controversial [50][51][52][53][54][55]. Finally, we have found that several commonly used pesticides inhibit the UPS and are associated with an increased risk of developing PD [7,13].…”

Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration

“…The numbers of SN TH-ir dopamine neurons did not appear to differ between the control and PSI-treated animals, nor did the density and pattern of the striatal innervation appear altered. Although we did not use stereological methods for the anatomical studies, given the magnitude of the dopamine cell loss reported in the original paper of McNaught et al (2004) as well as the two reports that found data consistent with PSI-induced DA cell loss (Schapira et al, 2006;Zeng et al, 2006) it is unlikely that a significant loss of SN dopaminergic neurons occured in our PSI-treated rats. Moreover, we failed to observe any significant decline in striatal dopamine concentrations in PSI-treated animals, suggesting that a stereological study of SN dopamine neurons was not warranted.…”

“…Moreover, decreased locomotor activity was reported to occur in response to PSI treatment. However, since this report three other papers have failed to replicate various aspects of the original findings (Bove et al, 2006;Kordower et al, 2006;Manning-Bog et al, 2006), while two other papers have replicated aspects of the orginal report (Schapira et al, 2006;Zeng et al, 2006).…”