Modulation of Notch Signaling Pathway to Prevent H

Authors: Maryam Kamarehei Razieh Yazdanparast

Publish Date: 2014/07/09

Volume: 34, Issue: 7, Pages: 1037-1045

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Abstract

The brain in Alzheimer’s disease is under increased oxidative stress and this may have a role in the pathogenesis and neural death in this disorder It has been verified that numerous signaling pathways involved in neurodegenerative disorders are activated in response to reactive oxygen species ROS EUK134 a synthetic salen–manganese antioxidant complex has been found to possess many interesting pharmacological activities awaiting exploration The present study is to characterize the role of Notch signaling in apoptotic cell death of SKNMC cells The cells were treated with hydrogen peroxide H2O2 or menadione to induce oxidative stress The freeradical scavenging capabilities of EUK134 were studied through the MTT assay glutathione peroxidase GPx enzyme activity assay and glutathione GSH Levels The extents of lipid peroxidation protein carbonyl formation and intracellular ROS levels as markers of oxidative stress were also studied Our results showed that H2O2/menadione reduced GSH levels and GPx activity However EUK134 protected cells against ROSinduced cell death by downregulation of lipid peroxidation and protein carbonyl formation as well as restoration of antioxidant enzymes activity ROS induced apoptosis and increased NICD and HES1 expression Inhibition of NICD production proved that Notch signaling is involved in apoptosis through p53 activation Moreover H2O2/menadione led to Numb protein downregulation which upon EUK134 pretreatment its level increased and subsequently prevented Notch pathway activation We indicated that EUK134 can be a promising candidate in designing naturalbased drugs for ROSinduced neurodegenerative diseases Collectively ROS activated Notch signaling in SKNMC cells leading to cell apoptosis

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