Mechanism of alcohol-induced oxidative stress and neuronal injury

Abstract

Neuro-cognitive deficits, neuronal injury, and neurodegeneration are well documented in alcoholics, yet the underlying mechanisms remain elusive. Oxidative damage of mitochondria and cellular proteins intertwines with the progression of neuroinflammation and neurological disorders initiated by alcohol abuse. Here, we present the evidence that metabolism of ethanol in primary human neurons by alcohol dehydrogenase (ADH) or cytochrome P450-2E1 (CYP2E1) generates reactive oxygen species (ROS) and nitric oxide (NO) via induction of NADPH/xanthine oxidase (NOX/XOX) and nitric oxide synthase (NOS) in human neurons. The acetaldehyde-mediated increase in NOX, XOX, or NOS activity is regulated as a transcriptional rather than a translational process. Marked increase in the lipid peroxidation product (4-hydroxynonenal) and enhanced ROS generation coincides with decreased neuronal viability and diminished expression of neuronal marker (neurofilaments). Novel quantitative methods of ROS and NO detection help dissect the mechanisms of alcohol-induced neurodegeneration. Uncovering the basic mechanisms of oxidative neuronal injury will serve as the basis for development of new therapies.

Citric acid reduces the decline in P300 amplitude induced by acute alcohol consumption in healthy adults

“…Although at low doses the effect of alcohol is not consistent, reaction time (RT) is generally slowed by the ingestion of alcohol indicating the slowing of mental processes (Liguori and Robinson, 2001;Martin and Siddle, 2003). Ethanol is converted into acetyl-CoA by liver enzymes and shuttled into the TCA cycle to be oxidized eventually (Haorah et al, 2008). Acetaldehyde, which is the first active metabolite of ethanol metabolized in the CNS through the actions of catalase, has locomotor stimulant properties when administered in the ventricular system of the brain or into specific brain nuclei (Correa et al, 2009).…”

Autophagy and ethanol neurotoxicity

“…[38][39][40] Because mitochondria are essential in regulating apoptosis, elimination of defective mitochondria by selective autophagy (mitophagy) is one of the mechanisms by which autophagy offers protection, 11,41 and ethanol increases mitophagy. 35 Ethanol-induced mitophagy is inhibited by BECN1 shRNA while it is increased by rapamycin.…”

Alcoholic lung injury: pineapple peel extract modulates antioxidant enzymes and attenuates lipid peroxidation in rat models

“…H 2 O 2 produced during alcohol metabolism to acetaldehyde by cytochrome P450-2E1 (CYP2E1) in both liver and lungs interacts with copper/iron leading to generation of Reactive Oxygen Species (ROS) and/or its products [4,5]. Oxidative stress sets in when there is an imbalance between oxidant (ROS) production and the system's ability to detoxify it in favour of the oxidants.…”