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Acetaldehyde‐Mediated Neurotoxicity
Author(s) -
Spaisman Amy,
Tong Ming,
Ding FeiFei,
Wands Jack,
Monte Suzanne
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a400-c
Subject(s) - acetaldehyde , oxidative stress , insulin , insulin receptor , chemistry , neurotoxicity , oxidative phosphorylation , ethanol , protein kinase b , mapk/erk pathway , microbiology and biotechnology , viability assay , dna damage , phosphorylation , biochemistry , biology , apoptosis , endocrinology , toxicity , insulin resistance , dna , organic chemistry
Background: Ethanol‐induced neuronal death is caused by impaired insulin signaling and mitochondrial (Mt) dysfunction. In liver, ethanol‐induced Mt dysfunction is mediated by acetaldehyde adduct formation. However, little is known about mechanisms of alcohol‐induced Mt failure in neurons. Objective: This study examines the role of acetaldehyde as a mediator of oxidative stress, Mt dysfunction and reduced insulin signaling in neuronal cells. Methods: Primary rat cerebellar neuron cultures were treated with 3.5 mM acetaldehyde, 50 mM ethanol or vehicle for 48 hours. Cultures were analyzed for Mt function, ATP content and viability using fluorescence‐based micro‐plate assays, and gene expression by quantitative RT‐PCR or cellular ELISA. Results: Acetaldehyde and ethanol both reduced neuronal viability, Mt function and ATP content, and increased oxidative stress and DNA damage. In contrast, ethanol and not acetaldehyde inhibited insulin stimulated Erk MAPK and Akt phosphorylation, and insulin‐responsive gene expression. While 4‐MP inhibition of ethanol metabolism reduced indices of oxidative stress, it did not restore insulin signaling. Conclusions: Ethanol‐induced oxidative stress/DNA damage and impairments in insulin signaling are caused by distinct mechanisms: the former by acetaldehyde, and the latter by inhibition of phosphorylation events required for insulin‐stimulated gene expression.