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Published ahead of print on February 25, 2003, doi:10.1164/rccm.200209-1050OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 11, June 2003, 1548-1553

A more recent version of this article appeared on June 1, 2003
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Submitted on September 17, 2002
Accepted on February 19, 2003

Intermittent Hypoxia Is Associated with Oxidative Stress And Spatial Learning Deficits in the Rat

Barry W Row1, Rugao Liu1, Wei Xu1, Leila Kheirandish1, and David Gozal2*

1 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA, 2 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

* To whom correspondence should be addressed. E-mail: david.gozal{at}louisville.edu.

In adult rats, exposure to intermittent hypoxia (IH), such as in sleep disordered breathing (SDB), leads to neurobehavioral impairments and increased apoptosis in the hippocampal CA1 region and cortex. We hypothesized that the episodic hypoxic-reoxygenation cycles of IH would induce oxidant stress, and underlie the IH-associated spatial learning and retention deficits. Male rats were therefore exposed to IH (90 sec alternations of 10% O2 and 21% O2) or room air (RA) for 7 days, received twice daily injections of either 3mg/kg of the anti-oxidant PNU-101033E (U) or vehicle (V), and trained in a standard place-training task in the water maze. V-IH displayed significant impairments of spatial learning which were attenuated by PNU-101033E. Post-hoc analyses further revealed that V-IH had significantly longer latencies and pathlengths to locate the hidden platform than PNU-IH, RA-C, or PNU-C, indicating that PNU-101033E treatment reduced the behavioral impairments associated with IH. Additionally, treatment with PNU-101033E markedly attenuated the increase in lipid peroxidation, and isoprostane concentrations associated with exposure to IH. Collectively, these findings indicate that the IH exposure is associated with increased oxidative stress, which is likely to play an important role in the behavioral impairments observed in a rodent model of SDB.
Key words: Intermittent hypoxia, sleep apnea, spatial learning, oxidative stress, sleep-disordered breathing




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