BHT Blocks NF-κB activation and Ethanol-Induced Brain Damage

Authors


  • This research is supported by Grants from NIAAA.

Reprint requests: Dr. Fulton T., Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, 1021 Thurston Bowles Building, CB 7178 Chapel Hill, NC 27599-7178; Fax: 919-966-5679; E-mail: ftcrews@med.unc.edu

Abstract

Background: Binge ethanol administration causes corticolimbic brain damage that models alcoholic neurodegeneration. The mechanism of binge ethanol-induced degeneration is unknown, but is not simple glutamate–N-methyl-d-aspartate (NMDA) excitotoxicity. To test the hypothesis that oxidative stress and inflammation are mechanisms of binge ethanol-induced brain damage, we administered 4 antioxidants, e.g., butylated hydroxytoluene (BHT), ebselen (Eb), vitamin E (VE), and blueberry (BB) extract, during binge ethanol treatment and assessed various measures of neurodegeneration.

Methods: Adult Sprague–Dawley rats were treated with intragastric ethanol 3 times per day (8–12 g/kg/d) alone or in combination with antioxidants or isocaloric diet for 4 days. Animals were killed, and brains were perfused and extracted for histochemical silver stain determination of brain damage, markers of neurogenesis, or other immunohistochemistry. Some animals were used for determination of nuclear factor κ B (NF-κB)–DNA binding by electrophoretic mobility shift assay (EMSA) or for reverse transcription–polymerase chain reaction (RT-PCR) of cyclooxygenase 2 (COX2).

Results: Binge ethanol induced corticolimbic brain damage and reduced neurogenesis. Treatment with BHT reversed binge induced brain damage and blocked ethanol inhibition of neurogenesis in all regions studied. Interestingly, the other antioxidants studied, e.g., Eb, VE, and BB, did not protect against binge-induced brain damage. Binge ethanol treatment also caused microglia activation, increased NF-κB–DNA binding and COX2 expression. Butylated hydroxytoluene reduced binge-induced NF-κB–DNA binding and COX2 expression.

Conclusions: Binge-induced brain damage and activation of NF-κB–DNA binding are blocked by BHT. These studies support a neuroinflammatory mechanism of binge ethanol-induced brain damage.

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