Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats.
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. Male rats consumed dextrin or 6.5% (wt/vol) ethanol for 35 days. During the last 20 days, rats were treated with repetitive (5-8 per 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 h 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. 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 with dextrin and ethanol per se, in the three brain regions, EW increased superoxide and protein carbonyl contents and accelerated PTP opening in a manner ameliorated by IH. Administration of antioxidant N-acetylcysteine throughout the IH program abrogated the reductions in EW signs and superoxide content, implicating IH-induced ROS as mediators of the salutary adaptations. We conclude that 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.
Jung
Marianna E
ME
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA.
Simpkins
James W
JW
Wilson
Andrew M
AM
Downey
H Fred
HF
Mallet
Robert T
RT
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000097:blood; D003912:Dextrins / Q000494:pharmacology; D004032:Diet; D000431:Ethanol / Q000009:adverse effects / Q000097:blood; D000860:Hypoxia / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D051336:Mitochondrial Membranes / Q000187:drug effects; D008933:Mitochondrial Swelling / Q000502:physiology; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D050050:Protein Carbonylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000523:psychology; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D002492:Central Nervous System Depressants; D003912:Dextrins; D016877:Oxidants; D013481:Superoxides; D000431:Ethanol; D000111:Acetylcysteine