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.

The CA1 and CA3 regions of the hippocampus markedly differ in their susceptibility to hypoxia in general, and more particularly to the intermittent hypoxia that characterizes sleep apnea. Proteomic approaches were used to identify proteins differentially expressed in the CA1 and CA3 regions of the rat hippocampus and to assess changes in protein expression following a 6-h exposure to intermittent hypoxia (IH). Ninetynine proteins were identified, and 15 were differentially expressed in the CA1 and the CA3 regions. Following IH, 32 proteins in the CA1 region and only 7 proteins in the more resistant CA3 area were up-regulated. Hypoxia-regulated proteins in the CA1 region included structural proteins, proteins related to apoptosis, primarily chaperone proteins, and proteins involved in cellular metabolic pathways. We conclude that IH-mediated CA1 injury results from complex interactions between pathways involving increased metabolism, induction of stress-induced proteins and apoptosis, and, ultimately, disruption of structural proteins and cell integrity. These findings provide initial insights into mechanisms underlying differences in susceptibility to hypoxia in neural tissue, and may allow for future delineation of interventional strategies aiming to enhance neuronal adaptation to IH. Keywords: apoptosis, intermittent hypoxia, neuronal vulnerability, obstructive sleep apnea, proteomics, rat hippocampus. Obstructive sleep apnea (OSA) is a condition characterized by repeated episodes of upper-airway obstruction during sleep, and affects 2-5% of the general population (National Heart and Blood Institute Working Group on Sleep Apnea 1996; Partinen and Telakivi 1992;Redline and Young 1993, Redline et al. 1994Redline and Strohl 1998). The major deleterious consequences of untreated OSA can be partitioned into two major groups, namely cardiovascular (Fletcher et al. 1992;Lavie et al. 1993;Fletcher 1995;Greenberg et al. 1999;Mooe et al. 2001) and neurocognitive morbidities (Kales et al. 1985;Roehrs et al. 1995;Gozal 1998). A major hallmark of OSA is the occurrence of intermittent hypoxia (IH) during sleep. We have recently established a rodent model whereby IH is associated with the typical neurocognitive deficits of OSA in the absence of sleep disturbances (Gozal et al. 2001). Indeed, IH slowed acquisition and impaired retention of a spatial reference task, but did not affect performance of non-spatial reference task as measured in the Morris water maze (Gozal et al. 2001). In addition, IH resulted in cellular changes and architectural disorganization in brain areas associated with neurocognitive function, such as the cortex and CA1 region of the hippocampus, but not the CA3 region of the hippocampal formation (Gozal et al. 2001). These findings are compatible with the concept of a slowly evolving, weak excitotoxicity process that may occur as a consequence of impaired cellular energy metabolism, free-radical production, and/or modifications in ion/receptor complexes (Albin and Greenamyre Received May 7, 2002;...

The effects of chronic sustained hypoxia (SH) on ventilation have been thoroughly studied. However, the effects of intermittent hypoxia (IH), a more prevalent condition in health and disease are currently unknown. We hypothesized that the ventilatory consequences of SH and IH may differ and be related to changes in N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression. To examine these issues, Sprague-Dawley adult male rats were exposed to 30 days of either SH (10% O2) or IH (21% and 10% O2 alternations every 90 s) or to normoxia (RA), at the end of which ventilatory and O2 consumption responses to a 20-min acute hypoxic challenge (10% O2) were conducted. In addition, dorsocaudal brain stem tissue lysates were harvested at 1 h, 6 h, 1 day, 3 days, 7 days, 14 days, and 30 days of SH and IH and analyzed for NR1, NR2A, and NR2B NMDA glutamate receptor expression by immunoblotting. Normoxic ventilation was higher after both SH and IH (P < 0.001). Peak hypoxic ventilatory response was higher after SH but not after IH compared with RA. However, hypoxic ventilatory decline was more prominent after SH than IH (P < 0.001). NR1 expression showed a biphasic pattern of expression over time that was essentially identical after IH and SH (P value not significant). However, NR2A and NR2B expression was higher in IH compared with SH and RA (P < 0.01). We conclude that long-lasting exposures to SH and IH enhance normoxic ventilation but are associated with different time domains of ventilation during acute hypoxia that may be accounted in part by changes in NMDA glutamate receptor subunit expression.