Abstract
It has been suggested that excessive reactive oxygen species (ROS) and oxidative stress play an important role in ethanol-induced damage to both the developing and mature central nervous system (CNS). The mechanisms underlying ethanol-induced neuronal ROS, however, remain unclear. In this study, we investigated the role of NADPH oxidase (NOX) in ethanol-induced ROS generation. We demonstrated that ethanol activated NOX and inhibition of NOX reduced ethanol-promoted ROS generation. Ethanol significantly increased the expression of p47phox and p67phox, the essential subunits for NOX activation in cultured neuronal cells and the cerebral cortex of infant mice. Ethanol caused serine phosphorylation and membrane translocation of p47phox and p67phox, which were prerequisites for NOX assembly and activation. Knocking down p47phox with the small interfering RNA was sufficient to attenuate ethanol-induced ROS production and ameliorate ethanol-mediated oxidative damage, which is indicated by a decrease in protein oxidation and lipid peroxidation. Ethanol activated cell division cycle 42 (Cdc42) and overexpression of a dominant negative (DN) Cdc42 abrogate ethanol-induced NOX activation and ROS generation. These results suggest that Cdc42-dependent NOX activation mediates ethanol-induced oxidative damages to neurons.
Highlights
Heavy alcohol consumption can cause structural and functional abnormalities of both the developing and mature brain [1,2]
To determine whether NOX is involved in ethanol-induced neuronal oxidative stress, we first examined the effect of ethanol on NADPH oxidase activity in vitro
reactive oxygen species (ROS) may be produced by multiple processes, such as mitochondrial electron transport chain and the activity of NOX, nitric oxide synthase, and xanthine oxidase [32]
Summary
Heavy alcohol consumption can cause structural and functional abnormalities of both the developing and mature brain [1,2]. Oxidative stress, which is caused by excessive production of reactive oxygen species (ROS), has been proposed as a potential mechanism for ethanol-induced neuronal damage [8,9,10,11,12]. The NOX family NADPH oxidases, enzymes that transfer electrons across biological membranes, are identified as a major source of cellular ROS [15]. Ethanol has been shown to up-regulate the expression NOX in many organs, including the lungs and liver, as well as in mouse embryos [18,19,20], suggesting that NOX may be involved in ethanolinduced ROS generation. We hypothesize that ethanol can activate NOX in neuronal cells, resulting in the accumulation of intracellular ROS. We demonstrated the involvement of cell division cycle 42 (Cdc42), a Rho-family GTPbinding protein (GTPase), in ethanol-induced NOX activation and ROS generation
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call