Submitted on February 25, 2008
Revised on May 21, 2008
Accepted on May 21, 2008
Intermittent Hypoxia Conditioning Prevents Behavioral Deficit and Brain Oxidative Stress in Ethanol Withdrawn Rats
Marianna E Jung1, James W Simpkins1, Andrew M Wilson1, H. Fred Downey2, and Robert T Mallet3*
1 Univ. North Texas Health Science Center
2 Univ. of North Texas Health Science Ctr. at Fort Worth
3 University of North Texas Health Science Center
* To whom correspondence should be addressed. E-mail: malletr{at}hsc.unt.edu.
Background: Intermittent hypoxia (IH) has been found to protect brain from ischemic injury. We investigated whether IH mitigates brain oxidative stress and behavioral deficits in rats subjected to ethanol intoxication and abrupt ethanol withdrawal (EW). The effects of IH on overt EW behavioral signs, superoxide generation, protein oxidation, and mitochondrial permeability transition pore (PTP) opening were examined. Methods: Male rats consumed dextrin or 6.5% (w/v) ethanol for 35 days. During the last 20 days, rats were treated with repetitive (5-8/day), brief (5-10 min) cycles of hypoxia (9.5-10% inspired O2) separated by 4 min normoxia exposures. Cerebellum, cortex and hippocampus were biopsied on day 35 of the diet or at 24 hours of EW. Superoxide and protein carbonyl contents in tissue homogenates and absorbance decline at 540 nm in mitochondrial suspensions served as indicators of oxidative stress, protein oxidation and PTP opening, respectively. Results: Although IH altered neither ethanol consumption nor blood ethanol concentration, it sharply lowered the severity of EW signs including tremor, tail rigidity, and startle response. Compared to dextrin and ethanol <I>per se</I>, in the 3 brain regions EW increased superoxide and protein carbonyl contents and accelerated PTP opening, in a manner ameliorated by IH. Administration of antioxidant <I>N</I>-acetylcysteine throughout the IH program abrogated the reductions in EW signs and superoxide content, implicating IH-induced ROS as mediators of the salutary adaptations. Conclusions: IH conditioning during chronic ethanol consumption attenuates oxidative damage to the brain and mitigates behavioral abnormalities during subsequent EW. IH-induced ROS may evoke this powerful protection.
