Rationale: The long-term intermittent hypoxia (LTIH) that characterizes sleep-disordered breathing impairs spatial learning and increases oxidative stress in rodents. We hypothesized that LTIH activated brain NADPH oxidase, which served as a critical Source Of Superoxide in the oxidation injury, and that apocynin might attenuate LTIH-induced spatial learning deficits by reducing LTIH-induced NADPH oxidase expression. Objective: To investigate the effects of apocynin on spatial learning and oxidative responses to LTIH in rats. Methods: Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of 10 each: a LTIH group, ail apocynin-treated LTIH group, a sham LTIH group and an apocynin-treated sham group. Spatial learning in each group was assessed with the Morris water maze test. RT-PCR and Western blot were used to examine mRNA and protein expression of NADPH oxidase Subunit p47phox and p22phox in the hippocampus region. The level of MDA and SOD were detected by colorimetric method. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to display the apoptotic cells of the hippocampus tissue. Results: Apocynin treatment prevented LTIH-induced decreases in spatial learning during the Morris water maze as well as LTIH-induced decrease in SOD levels. In untreated animals, LTIH exposure was related to increase of MDA levels in comparison to sham LTIH animals, and apocynin-treated animal exposure to LTIH showed reduction in MDA levels. Increases in hippocampus NADPH oxidase Subunit p47phox mRNA and protein expression were observed in LTIH-exposed animals: there was no statistical difference of p47phox mRNA and protein expression between LTIH group and apocynin treatment group. Treatment with apocynin significantly ameliorated cell apoptosis in LTIH-exposed animals. conclusion: These results indicate that apocynin attenuates LTIH-induced spatial learning deficits and mitigates LTIH-induced oxidative stress through Multiple beneficial effects oil oxidant pathways. NADPH oxidase up-expression is closely associated with oxidative processes in LTIH rats, and inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for cognitive function impairment from chronic intermittent hypoxia. (C) 2009 Elsevier B.V. All rights reserved.