A novel mechanism for pergolide-induced neuroprotection: inhibition of NF-kappaB nuclear translocation.
We previously demonstrated that the dopaminergic agonist pergolide, independently from its DA agonist activity, can exert neuroprotective effects against cell death induced in SH-SY5Y neural cells by H(2)O(2) treatment. Since oxidative stress in SH-SY5Y neural cells is known to activate the NF-kappaB pathway we tested the hypothesis that pergolide may interfere with NF-kappaB activity. Based on Western blot analysis and immunocytochemistry, pergolide was found to prevent H(2)O(2)-induced apoptosis by inhibiting NF-kappaB nuclear translocation and activation of p53 signalling pathway. Similarly, the cell-permeable SN50 peptide, which is known to block NF-kappaB nuclear translocation, prevented both H(2)O(2)-induced p53 expression and apoptosis. The mechanism of action of pergolide responsible for neuroprotection differed from that of antioxidants. In fact, Vitamin E, contrary to pergolide and SN50, rescued neuronal cells from H(2)O(2)-induced apoptosis acting upstream NF-kappaB activation, as demonstrated by the prevention of H(2)O(2)-induced IkappaB degradation. These data suggest a novel site of action of pergolide that may account for additional pharmacological properties of this drug.
Uberti
D
D
Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Carsana
T
T
Francisconi
S
S
Ferrari Toninelli
G
G
Canonico
P L
PL
Memo
M
M
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000704:Analysis of Variance; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D010479:Pergolide / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D016328:NF-kappa B; D018696:Neuroprotective Agents; D010455:Peptides; C118258:SN50 peptide; D016159:Tumor Suppressor Protein p53; D014810:Vitamin E; D010479:Pergolide