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
PBN-AR
Instytucja
Instytut Farmakologii im. Jerzego Maja Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
angielski
Czasopismo
NEUROTOXICITY RESEARCH
ISSN
1029-8428
EISSN
1476-3524
Wydawca
SPRINGER
DOI
Rok publikacji
2014
Numer zeszytu
3
Strony od-do
255-273
Numer tomu
26
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Słowa kluczowe
en
Celastrol;
Dopamine;
Lactacystin;
Parkinson's disease;
SH-SY5Y cells;
Substantia nigra
Open access
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en
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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 mu g/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with lactacystin (5 mu g/2 mu l) 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.
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PX-56989cd3810641ecf9198e73
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