Mechanism of alcohol-induced oxidative stress and neuronal injury.
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.
Haorah
James
J
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. jhaorah@unmc.edu
Ramirez
Servio H
SH
Floreani
Nicholas
N
Gorantla
Santhi
S
Morsey
Brenda
B
Persidsky
Yuri
Y
D000079:Acetaldehyde / Q000494:pharmacology*; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D000447:Aldehydes; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000431:Ethanol; D009249:NADP; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal