Published ahead of print on May 28, 2003, doi:10.1164/rccm.200211-1264OC
Am. J. Respir. Crit. Care Med., Volume 168, Number 4, August 2003, 469-475
A more recent version of this article appeared on August 15, 2003
Submitted on November 4, 2002
Accepted on May 21, 2003
CYCLOOXYGENASE 2 AND INTERMITTENT HYPOXIA-INDUCED SPATIAL DEFICITS IN THE RAT
Richard C Li1, Barry W Row1, Evelyne Gozal2, Leila Kheirandish1, Qiang Fan1, Kenneth R Brittian1, Shang Z Guo1, Leroy R Sachleben Jr1, and David Gozal2*
1 Pediatrics, University of Louisville, Kosair Children's Hospital Research Institute, Louisville, KY, USA,
2 Pediatrics, University of Louisville, Kosair Children's Hospital Research Institute, Louisville, KY, USA; Pharmacology and Toxicology, University of Louisville, Kosair Children's Hospital Research Institute, Louisville, KY, USA
* To whom correspondence should be addressed. 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. 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 gene and COX-2 protein expression and activity (PGE2 tissue concentration) in cortical regions of rat brain after exposure to either IH (10% O2 alternating with 21% O2 every 90 sec) or sustained hypoxia (CH; 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 CH or IH. IH-induced COX-2 up-regulation 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 up-regulation 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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