|Crews, Fulton - UNC-CH|
|Nixon, Kimberly - UNIVERSITY OF KENTUCKY|
|Kim, Daniel - UNC-CH|
|Qin, Liya - UNC-CH|
|Zou, Jian - UNC-CH|
Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 31, 2006
Publication Date: November 1, 2006
Citation: Crews, F.T., Nixon, K., Kim, D., Joseph, J.A., Shukitt Hale, B., Qin, L., Zou, J. 2006. Bht blocks nfkb activation and ethanol-induced brain damage. Alcoholism: Clinical and Experimental.30(11):1938-1949. Interpretive Summary: Binge ethanol administration causes brain damage that models alcoholic brain degeneration. The mechanism of binge ethanol induced degeneration (cell loss) is unknow. We hypothesize that oxidative stress (excess free radicals) and inflammation are causes of binge ethanol induced brain damage. To test the hypothesis, we administered four antioxidants: vitamin E extract, blueberry extract, butylated hydroxytoluene (BHT), a common food additive, and ebselen (Eb), a commerical product that reduces ethanol induced liver damage, during binge ethanol treatment and measured brain degeneration. Adult rats were treated with ethanol three times per day alone, in combination with antioxidants or a diet without antioxidants but containing the same caloric value for four days. Animals were sacrificed and the amount of brain damage and indications of new brain cell growth were measures. Some animals were used to determine the quantity of chemical factor associated with inflammatory response. The results showed that binge ethanol induced brain damage and reduced the amount of new brain cell growth. Treatment with BHT reversed binge induced brain damage and blocked the binge ethanol induced reduction of new brain cell growth. Binge ethanol treament also caused an activation of cells that remove dying or damaged cells and increased activity of the chemical factory associated with inflammatory respose. BHT blocked the binge induced activity of the chemical factory associated with inflammatory response. This study suports inflammatory resposnses as causing binge ethanol induced brain damage.
Technical Abstract: Binge ethanol administration causes corticolimbic brain damage that models alcoholic neurodegeneration. The mechanism of binge ethanol induced degeneration is unknown, but is not glutamate neurotoxicity. To test the hypothesis that oxidative stress and inflammation are mechanisms of binge ethanol induced brain damage we administered four antioxidants, e.g. butylated hydroxytoluene (BHT), ebselen (Eb), vitamin E (VE) and blueberry (BB) extract , during binge ethanol treatment and measured neurodegeneration. Adult Sprague-Dawley rats were treated with intragastric ethanol 3 times per day (8-12 g/kg/day) alone or in combination with antioxidants, or isocaloric diet for four days. Animals were sacrificed, brains perfused and extracted for histochemical silver stain determination of brain damage, markers of neurogenesis or other histochemistry. Some animals were used for determination of NfkB-DNA binding by EMSA. Binge ethanol induced corticolimbic brain damage and reduced neurogenesis. Treatment with BHT reversed binge induced brain damage and block 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 a microglia activation and increased NfkB-DNA binding activity. BHT blocked binge induced NfkB-DNA binding. Conclusions: Binge induced brain damage and activation of NfkB-DNA binding are blocked by BHT. These studies support a neuroinflammatory mechanism of binge ethanol induced brain damage.