Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat.
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.
Li
Richard C
RC
Kosair Children's Hospital Research Institute, 570 South Preston Street, Suite 321, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
Row
Barry W
BW
Gozal
Evelyne
E
Kheirandish
Leila
L
Fan
Qiang
Q
Brittian
Kenneth R
KR
Guo
Shang Z
SZ
Sachleben
Leroy R
LR
Gozal
David
D
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002540:Cerebral Cortex / Q000201:enzymology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia / Q000150:complications / Q000201:enzymology*; D007527:Isoenzymes / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D018782:Maze Learning; D008565:Membrane Proteins; D008569:Memory Disorders / Q000201:enzymology* / Q000209:etiology; D009474:Neurons / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology; D010544:Peroxidases / Q000032:analysis* / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis* / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012891:Sleep Apnea Syndromes / Q000150:complications / Q000201:enzymology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010544:Peroxidases; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone