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Cyclooxygenase 2 and Intermittent Hypoxia-induced Spatial Deficits in the Rat

Kosair Children's Hospital Research Institute, Department of Pediatrics, and Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky

Correspondence and requests for reprints should be addressed to David Gozal, M.D., Kosair Children's Hospital Research Institute, 570 South Preston Street, Suite 321, Department of Pediatrics, University of Louisville, Louisville, KY 40202. E-mail: david.gozal{at}louisville.edu

Intermittent hypoxia (IH) during sleep, a critical feature of sleep apnea, induces significant neurobehavioral deficits in the rat. Cyclooxygenase (COX)-2 is induced during stressful conditions such as cerebral ischemia and could play an important role in IH-induced learning deficits. We therefore examined COX-1 and COX-2 genes and COX-2 protein expression and activity (prostaglandin E2 [PGE2] tissue concentration) in cortical regions of rat brain after exposure to either IH (10% O₂ alternating with 21% O₂ every 90 seconds) or sustained hypoxia (10% O₂). In addition, the effect of selective COX-2 inhibition with NS-398 on IH-induced neurobehavioral deficits was assessed. IH was associated with increased COX-2 protein and gene expression from Day 1 to Day 14 of exposure. No changes were found in COX-1 gene expression after exposure to hypoxia. IH-induced COX-2 upregulation was associated with increased PGE2 tissue levels, neuronal apoptosis, and neurobehavioral deficits. Administration of NS-398 abolished IH-induced apoptosis and PGE2 increases without modifying COX-2 mRNA expression. Furthermore, NS-398 treatment attenuated IH-induced deficits in the acquisition and retention of a spatial task in the water maze. We conclude that IH induces upregulation and activation of COX-2 in rat cortex and that COX-2 may play a role in IH-mediated neurobehavioral deficits.

Key Words: sleep apnea • neurocognitive deficits • inflammation • episodic hypoxia

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