A novel mechanism for pergolide-induced neuroprotection:: inhibition of NF-κB 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 H2O2 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 H2O2-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 H2O2-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 H2O2-induced apoptosis acting upstream NF-kappaB activation, as demonstrated by the prevention of H2O2-induced IkappaB degradation. These data suggest a novel site of action of pergolide that may account for additional pharmacological properties of this drug. (C) 2004 Elsevier Inc. All rights reserved.