Modulation of H2O2-induced mitogen-activated protein kinases activation and cell death in SK-N-MC cells by EUK134, a salen derivative

Abstract

Alzheimer's disease is a neurodegenerative disorder that is characterized by the accumulation of senile plaques containing amyloid β (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain. Oxidative stress has been proposed to mediate Aβ-induced neurotoxicity. In that regard, we evaluated the ability of EUK134, a superoxide dismutase and catalase mimics, to protect human neuroblastoma cell line SK-N-MC against H2O2-induced oxidative stress. Our data clearly indicated that cell death induced by H2O2 was reversed by EUK134. Likewise, lipid peroxidation, caspase-3 activation and intracellular reactive oxygen species formation all returned to control levels following pre-treatments with EUK134. Elevated phosphorylation of mitogen-activated protein kinases (MAPK) induced by H2O2 in SK-N-MC cells was lowered by EUK134 in a dose-dependent manner. In addition, EUK134 decreased expression of pro-apoptotic genes p53 and Bax and enhanced expression of anti-apoptotic Bcl-2 gene. Taken together, these results suggest that EUK134 protects neuronal cells against H2O2 toxicity by attenuating oxidative stress through inhibition of MAPK phosphorylation cascade. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.