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Acetate, an Ethanol Metabolite Increases Neuroinflammation and Neuronal Death: Implications in Ethanol Neurodegeneration
Author(s) -
Chapp Andrew D.,
Driscoll Kyle M.,
Behnke Jessica,
Shan Zhiying,
Chen Qinghui
Publication year - 2017
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.31.1_supplement.1061.4
Subject(s) - excitotoxicity , chemistry , apoptosis , neuroinflammation , neurodegeneration , neurotoxicity , propidium iodide , metabolite , neuroprotection , programmed cell death , pharmacology , biochemistry , medicine , biology , toxicity , inflammation , disease , organic chemistry
Upregulation of neuroinflammatory signaling molecules following ethanol consumption has been identified as a key cellular mechanism to contribute to neuronal excitotoxicity. Evidence indicates that ethanol excitotoxicity occurs during ethanol withdrawal/clearance, times at which acetate concentrations are still elevated. Studies have demonstrated that acetate is a very active and powerful metabolite of ethanol, which may be one of the key components to underlie the mechanisms of neuronal excitotoxicity/apoptosis induced by ethanol consumption. Here, we tested the hypothesis that acetate increases neuroinflammatory cytokines, which may contribute to neuronal excitotoxicity/apoptosis and enhanced cellular death. Whole brain neuronal cultures incubated with acetate (2 mM) for 3 hrs. increased mRNA levels significantly (p < 0.05 vs control) of tumor necrosis factor alpha (TNFα), interleukin‐1β (IL‐1β) and fos related antigen 1 (fosl1); 2 fold, 8 fold and 2 fold respectively. Furthermore, 24 hr. treatment with acetate (2 mM) in whole brain neuronal cultures followed by staining with propidium iodide and analyzed via flow cytometry (1000 neurons, triplicates) showed significant neuronal death (p < 0.05 vs control), acetate (62.3 %) vs control (25.5 %). In a separate treatment, whole brain neuronal cultures were incubated with acetate (2 mM) for 24 hrs. and then stained with Fluo‐4AM (calcium dye) and analyzed via flow cytometry (1000 neurons, triplicates) and showed a significant 5 % increases in cytosolic calcium (p < 0.05 vs control). This data suggests that physiological circulating levels of acetate (2 mM) following ethanol consumption and metabolism lead to increased neuroinflammation which enhances whole brain cellular apoptosis/death and may be the underlying cause of alcohol associated neurodegeneration. Support or Funding Information AHA 16PRE27780121, Andrew Chapp, AHA 11SDG7420029, Zhiying Shan; R15‐HL122952, Qinghui Chen