Lack of neuroprotective effect of celastrol under conditions of proteasome inhibition by lactacystin in in vitro and in vivo studies: implications for Parkinson's disease.
A number of studies suggest that the ubiquitin-proteasome system (UPS) impairment may underlie neuronal death in Parkinson's disease. Celastrol is a neuroprotective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cortical neurons and neuroblastoma SH-SY5Y cells were incubated with lactacystin for 48 h (2.5 and 10 μg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with lactacystin (5 μg/2 μl) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects of celastrol, given either in the pre- or co-treatment mode. Moreover, in the higher concentrations, celastrol itself reduced cell viability, and enhanced the lactacystin-induced cell death in both types of cells. In the in vivo study, none of the celastrol doses (0.3-3 mg/kg) attenuated the lactacystin-induced decrease in the level of dopamine (DA) and its metabolites or protected nigral dopaminergic neurons against the lactacystin-induced degeneration. The highest celastrol dose potentiated the lactacystin-induced decrease in the level of DA and its metabolites in the lesioned striatum, and accelerated the lactacystin-induced increase in the oxidative and total metabolism of DA. Moreover, when given alone, this dose of celastrol bilaterally decreased the number and/or density of dopaminergic neurons in the SN. Our results demonstrate that celastrol does not induce neuroprotective effects under conditions of UPS inhibition.
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12 St., 31-343, Kraków, Poland, koniecz@if-pan.krakow.pl.
Jolanta
J
Konieczny
Danuta
D
Jantas
Tomasz
T
Lenda
Helena
H
Domin
Anna
A
Czarnecka
Katarzyna
K
Kuter
Maria
M
Śmiałowska
Władysław
W
Lasoń
Elżbieta
E
Lorenc-Koci
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D061988:Proteasome Inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014315:Triterpenes / Q000494:pharmacology*
D018696:Neuroprotective Agents; D053978:Pentacyclic Triterpenes; D061988:Proteasome Inhibitors; D014315:Triterpenes; C067713:lactacystin; C050414:celastrol; D004298:Dopamine; D000111:Acetylcysteine