Attenuation of NF-κB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis

Abstract

Oxidative stress has been implicated in the etiology of neurodegenerative diseases and aging. Indeed, accumulation of reactive oxygen species, such as hydrogen peroxide, generated by inflammatory cells, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders of the central nervous system, such as Alzheimer's disease. The present study indicates that H(2)O(2)-induced cell death can be inhibited in the presence of 1,2,4-triazine derivatives, as measured by MTT and caspase-3 activity. We further show that these compounds exert their protective effect by up-regulation of hemeoxygenase-1, glutamylcysteine synthetase, glutathione peroxidase and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), while they inhibit NF-kappaB and decrease lipid peroxidation. It shows that there is a potential cross talk between NF-kappaB and Nrf2, an important cytoprotective transcription factor in the presence of these compounds. Moreover, in order for drugs to be effective in the treatment of neurodegenerative diseases, they must be capable of penetrating the blood-brain barrier, whereas more than 98% of all potential central nervous system drugs don't cross. Using a reliable model based on the artificial neural network indicated that these compounds satisfy this requirement.

Antioxidant and antiglycating activities of Salvia sahendica and its protective effect against oxidative stress in neuron-like PC12 cells

“…However, this increase starts to decrease after a while [2,29]. To determine whether S. sahendica induces HO-1 or not, PC12 neurons were pretreated with 10, 25, 50 and 100 lg/ml of plant extract for 24 h and then exposed to H 2 O 2 .…”

“…Oxidative damage is mediated by reactive oxygen species (ROS) which are generated following cell lysis, oxidative burst or presence of excess free transition metals. Hydrogen peroxide (H 2 O 2 ), one of the main ROS, is produced during the redox process and has recently been considered as a messenger in intracellular signaling cascades which can cause lipid peroxidation and DNA damage, thus inducing apoptosis in many different cell types, including PC12 cells [2]. Therefore, therapeutic strategies aimed at preventing or delaying ROS-induced apoptosis might be a reasonable approach to treating AD.…”

S. choloroleuca, S. mirzayanii and S. santolinifolia protect PC12 cells from H2O2-induced apoptosis by blocking the intrinsic pathway

“…evaluate the detailed mechanism of this cytoprotection, we previously examined antioxidant and antiglycating activities of these plants. The overexpression of antioxidant enzymes such as catalase and super oxide dismutase, as well as the reduction of lipid peroxidation and protein glycation, are the primary mechanisms of cell defense in oxidative stress conditions (Tusi et al 2010). In our previous study we confirmed that all of these mechanisms are triggered by Salvia species in cells exposed to H 2 O 2 (Asadi et al ).…”

Immunomodulatory activities of alpha lipoic acid with a special focus on its efficacy in preventing miscarriage

“…The inhibition of NF-kB translocation from the cytoplasm to the nucleus assumes a pivotal role in reducing uncontrolled oxidative and inflammatory reactions. Some evidences indicate that a cross talk between Nrf2 and NF-kB exists [58]. This is an important issue according to the relationship with the cascade of events triggered by some immunomodulators.…”