help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on February 25, 2003, doi:10.1164/rccm.200209-1050OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200209-1050OCv1
167/11/1548    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Row, B. W.
Right arrow Articles by Gozal, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Row, B. W.
Right arrow Articles by Gozal, D.
American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1548-1553, (2003)
© 2003 American Thoracic Society

Original Article

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

Barry W. Row, Rugao Liu, Wei Xu, Leila Kheirandish and David Gozal

Department of Pediatrics, Kosair Children's Hospital Research Institute; and Department of Pharmacology & 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, University of Louisville, Baxter Biomedical Research Building, Suite 321, 570 South Preston Street, Louisville, KY 40202. E-mail: david.gozal{at}louisville.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the adult rat, exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with 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 the latter may underlie the IH-associated spatial learning and retention deficits. Adult male rats were therefore exposed to IH (90-second alternations of 10% oxygen and 21% oxygen) or room air (RA) for 7 days, and received twice-daily injections of either 3 mg/kg of the antioxidant PNU-101033E (PNU) or vehicle (V). Rats were then trained in a standard place-training task in the water maze. V-IH displayed significant impairments of spatial learning in the water maze, 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, V-RA, or PNU-RA, indicating that PNU-101033E treatment reduced the behavioral impairments associated with IH. In addition, 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 sleep-disordered breathing.

Key Words: intermittent hypoxia • sleep apnea • spatial learning • oxidative stress • sleep-disordered breathing

Over the last 20 years, a substantial body of evidence has accumulated to indicate that sleep-disordered breathing (SDB) is a growing health problem in both adult and pediatric populations (1–3). Recent estimates suggest that as much as 5% of the general population may suffer from the most common form of SDB, obstructive sleep apnea (4). The clinical syndrome of obstructive sleep apnea is characterized by repeated episodes of upper airway obstruction during sleep and substantial neuropsychological impairments in humans (5). Chronic exposure to intermittent hypoxia (IH), such as encountered in obstructive sleep apnea, is marked by neurodegenerative changes in both the adult and developing rat brain. Most notable are increases in programmed cell death in the CA1 region of the hippocampus and adjacent cortex as well as impaired spatial learning in the Morris water maze (6–8). The sensitivity of the hippocampus to hypoxic insults and its well established role as a critical structure for learning and memory suggests that exposure to IH may play a significant role in the cognitive disturbances seen in patients with obstructive sleep apnea (9).

Oxidative stress is associated with spatial learning impairments in the rat, has been implicated in the pathophysiological mechanisms underlying several neurodegenerative brain disorders, and enhances neuronal susceptibility to glutamate excitotoxicity (10–13). Hypoxia and ischemia are associated with increased release of glutamate (14) as well as with increased oxygen (O2) radical production and membrane lipid peroxidation (14–17), suggesting that oxidative stress is a potential contributor to the cellular injury and behavioral impairments associated with IH. Therefore, the present study was undertaken to determine whether IH is associated with increased lipid peroxidation in cortical tissue and whether administration of an antioxidant will attenuate the behavioral impairments associated with IH in the adult rat.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Behavioral experiments were performed on 36 young adult male Sprague–Dawley rats (175–200 g). An additional set of 24 adult male Sprague–Dawley rats (175–200 g) were used to assess lipid peroxidation. Animals were housed in groups of four in clear polycarbonate cages (55 x 45 x 35 cm) with food and water available ad libitum. Rats were randomly assigned to be housed in IH (n = 18) or room air (RA, n = 18). Starting 1 day before IH exposure, each animal received twice-daily injections (8:00 A.M. and 8:00 P.M.) of either 3 mg/kg of PNU-101033E (PNU, n = 9) or vehicle (V, n = 9). Animals in all four conditions (V-IH, PNU-IH, V-RA, and PNU-RA) were kept on a 12-hour light/dark schedule (6:00 A.M.–6:00 P.M.), and all behavioral testing was conducted during the light phase. The experimental protocols were approved by the Institutional Animal Use and Care Committee and are in close agreement with the National Institutes of Health guide for the care and use of laboratory animals. All efforts were made to minimize animal suffering and to reduce the number of animals used.

Intermittent Hypoxia
Animals were maintained in 4 identical commercially designed chambers (0.762 x 0.508 x 0.508 m, Oxycycler model A44XO; BioSpherix, Redfield, NY) operated under a 12 hour light–dark cycle (6:00 A.M.–6:00 P.M.) for 7 days before behavioral testing. O2 concentration was continuously measured by an O2 analyzer and was changed by a computerized system controlling gas outlets, as described previously (7, 8), such as to generate either a cyclical pattern of 10 and 21% O2 every 90 seconds (IH) during the sleep cycle, or of 21% throughout (RA). Ambient temperature was kept at 22–24°C.

Behavioral Testing
The mammalian hippocampus plays a central role in spatial as well as declarative/relational, and epidosic memory in rats and both human and nonhuman primates, and selective deficits in declarative or explicit memory are associated with neuronal loss/damage to the CA1 region hippocampus in humans (18).

Spatial learning was assessed in a Morris water maze (180 cm in diameter, filled to a depth of 50 cm, and maintained at 23 ± 1°C) as described previously (6, 7). Behavioral testing consisted of a standard place-training reference memory task in the water maze. Rats were trained to locate a hidden, submerged platform while only using distal spatial cues. For each trial, the rat was placed into the pool from quasirandom start points (N, S, E, or W) and allowed a maximum of 90 seconds to escape to the platform, where it was allowed to remain for 15 seconds. Training consisted of one eight-trial training session, followed by a four-trial retention session 24 hours later. Cued training was also conducted on the last day of place training to test for group differences in sensorimotor and motivational factors. Cued training consisted of one session of three trials. During these trials, a visible platform was placed in a different location within the pool on each trial. Each rat was given 30 seconds to locate the platform, and the animal was allowed to remain on the platform for 5 seconds. Each cued trial was separated by a 30-second intertrial interval. Mean escape latencies, swim distances, and swim speeds were analyzed by a repeated-measures analysis of variance and used to measure performance in the water maze. Student–Newman–Keuls' post hoc tests were used when appropriate. A p value less than 0.05 was considered statistically significant.

Lipid Peroxidation Assay
An LPO-586 kit (OxisResearch, Portland, OR) was used to measure the relative malondialdehyde production, a commonly used indicator of lipid peroxidation (19), in rat brain cortex according to the manufacturer's instructions. Briefly, after anesthesia with pentobarbital (50 mg/kg intraperitoneally), the laboratory animals were perfused with 0.9% saline buffer for 5 minutes and the cortex was dissected, snap frozen in liquid nitrogen, and stored at -80°C until assay the next day. Cortical tissues were homogenized in 20 mM phosphate buffer (pH 7.4) containing 0.5 mM butylated hydroxytoluene to prevent sample oxidation. After protein concentration measurement, equal amounts of proteins (2.0–2.5 mg proteins from each sample) in triplicates were used to react with chromogenic reagents at 45°C in 500 µl buffer for 1–2 hours. The samples were then centrifuged, and clear supernatants were measured at 586 nm. The level of malondialdehyde production was calculated with the standard curve according to the manufacturer's instructions (OxisResearch).

Isoprostane Tissue Measurements
The presence of 15-isoprostane F2 and related metabolites was examined using the Oxford Biomedical Research ELISA kit (cat #EA84) in tissue samples, after solid phase extraction of the isoprostane-containing fraction as recommended by the manufacturer (see online supplement).

Immunohistochemical Studies
Three rats exposed to either RA or to IH for 7 days were anesthetized with pentobarbital (100 mg/kg) and perfused with 4% paraformaldehyde for 2 hours. Sections of hippocampus were immunostained with a monoclonal anti-8-hydroxy-2'-deoxyguanosine/8-hydroxyguanosine antibody (oxo8dG/oxo8G; 1:2,000; QED Bioscience, San Diego, CA) as described previously (20).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
On a standard place-discrimination task, V-IH exhibited longer latencies and pathlengths to locate the hidden platform compared with PNU-IH, V-RA, and PNU-RA animals (Figure 1) . Analysis of variance revealed significant treatment (IH) by trial block interactions for both latency (F(3,31) = 3.868, p < 0.02) and pathlength (F(3,31) = 4.65, p < 0.01). Post hoc analyses showed that V-IH rats were significantly impaired on both latency and pathlength with respect to all other groups on trial block 3 (p < 0.05).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. (Right panel) Mean latencies (seconds) to locate the target platform during place training in rats exposed to 7 days of intermittent hypoxia (IH) and treated with vehicle (open squares, n = 9) or PNU-101033E (filled squares, n = 9) and control animals housed in room air (RA) and treated with vehicle (open circles, n = 9) or PNU-101033E (filled circles, n = 8). (Left panel) Mean swim distances (cm) to locate the target platform during place training in rats exposed to 7 days of IH and treated with vehicle (open squares, n = 9) or PNU-101033E (filled squares, n = 9) and control animals housed in RA and treated with vehicle (open circles, n = 8) or PNU-101033E (filled circles, n = 6).

 
No significant group differences in swimming speed and in performance during the cued task occurred among the four groups, indicating that the observed differences were not due to sensorimotor or motivational differences among the groups (Figure 2) .



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. (Left panel) Mean latencies (seconds) to locate the target platform during cued training in rats exposed to 7 days of IH and treated with vehicle (open circles, n = 9) or PNU-101033E (filled circles, n = 9) and control animals housed in RA and treated with vehicle (open circles, n = 9) or PNU-101033E (filled circles, n = 9). (Right panel) Mean swim distances (cm) to locate the target platform during cued training in rats exposed to 7 days of IH and treated with vehicle (open circles, n = 9) or PNU-101033E (filled circles, n = 9) and control animals housed in RA and treated with vehicle (open circles, n = 9) or PNU-101033E (filled circles, n = 9).

 
In a separate group of rats (n = 6 per time point), IH exposures was associated with significant increases in the relative malondialdehyde production in the cortex of rats exposed to 7 days of IH (p < 0.01 vs. RA; Figure 3) . The amount of malondialdehyde production in animals exposed to 7 days of IH-treated with the antioxidant PNU-101033E was not significantly different from control animals (not significant vs. RA), indicating that the compound effectively crossed the blood–brain barrier and reduced cortical tissue lipid peroxidation.



View larger version (57K):
[in this window]
[in a new window]
  		Figure 3. Relative fold changes in malondialdehyde (MDA) production in rats exposed to IH for 1 day (open bar), 3 days (diagonally hatched bar), and 7 days (black bar) and 7 days IH with daily injections of the antioxidant PNU-101033E (vertically hatched bars) compared with RA control animals (n = 6 per group; *, IH vs. control, p value less than 0.05, Student's t test).

 
Similarly, time-dependent increases in the tissue concentrations of 15-isoprostane F2 and related metabolites occurred during IH, and were blocked by PNU-101033E treatment (Figure 4) . In addition, marked increases in oxo8dG/oxo8G immunoreactivity were apparent in IH-exposed rats, and staining was particularly localized within the cytosol, suggestive of RNA oxidant damage (Figure 5) .



View larger version (42K):
[in this window]
[in a new window]
  		Figure 4. Cortical tissue concentrations of 15-isoprostane F2 and related metabolites in rats exposed for 1 day, 3 days, and 7 days in IH and 7 days IH with daily injections of the antioxidant PNU-101033E compared with RA control animals (n = 6 per group; *, IH [any time point] vs. RA, p < 0.01 analysis of variance [ANOVA]; #, IH7 vs. IH7-PNU, p value less than 0.001, Student's t test).

 


View larger version (152K):
[in this window]
[in a new window]
  		Figure 5. IH exposure is associated with RNA oxidative damage in the hippocampus. Representative hippocampal sections from rats exposed to RA (A) and (B) or 7 days of IH (C) and (D), immunostained with a monoclonal anti-8-hydroxy-2'-deoxyguanosine/8-hydroxyguanosine antibody.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Oxidative stress is a well established mechanism of cellular injury in mammals. Brain tissue contains a large amount of polyunsaturated fatty acids, which are highly susceptible to oxidative reactions. Thus, lipid peroxidation is a common form of oxidative stress in the brain (19). Oxidative stress and increased gliosis have been associated with aging related behavioral impairments on spatial learning tasks in the rodent (13), and similar increases in gliosis in the cortex and hippocampal CA1 region have been observed in the rat after exposure to IH (7). In the present study, we demonstrate that IH is associated with significant increases in lipid peroxidation and oxidant stress in brain tissue, and that administration of the antioxidant, PNU-101033E, attenuates the spatial learning deficits associated with exposure to IH. These findings provide initial support to the concept that oxidative stress contributes to the cellular damage and consequent behavioral impairments associated with severe forms of SDB.

Before we address the potential significance of our findings, some methodological comments are needed. The rodent model used in the present study clearly does not incorporate all of the potentially injurious elements contained within the spectrum of SDB in humans. More specifically, only IH occurs in the animal model (7), whereas patients with SDB sustain alveolar hypoventilation and sleep fragmentation in addition to the episodic hypoxemia. Thus, it is possible that interactions between these three potentially injurious components of SDB may either accentuate or abate the neurocognitive consequences of IH observed in the present study (21). Second, there has been substantial disagreement as to whether SDB indeed leads to neurocognitive deficits or whether such deficits are primarily due to impaired vigilance (21). Recent imaging studies in patients with SDB would suggest that substantial gray matter loss occurs bilaterally in areas associated with cognitive function, thereby lending credit to the possibility that episodic hypoxemia will not only induce neuronal deficits in rodents, but also in humans (22).

Glutamate excitotoxicity has been implicated in hypoxia/ischemia-induced neuronal damage (23–25), and a chronic, slowly evolving form of glutamate excitotoxicity has been proposed as one of the potential mechanisms by which IH induces neurodegenerative changes in the brain (7, 8). Both hypoxia and ischemia will induce increased release of excitatory amino acids, such as glutamate (14), potentially leading to excessive activation of ionotropic N-methyl-D-aspartate (NMDA) receptors and eventually resulting in programmed cell death (14, 26, 27). This is consistent with findings that NMDA glutamate receptor–expressing cells within the hippocampus appear to be especially vulnerable to IH, as evidenced by reductions in NMDA receptor immunoreactivity after IH (7), alterations in NMDA NR2 receptor subunit expression (28), as well as reductions in NMDA glutamate receptor binding sites in the hippocampus after hypobaric hypoxia (29). In addition, NMDA receptor antagonists exert a neuroprotective effect in hypoxia/ischemia-induced neuronal damage and oxidant tissue injury (30, 31).

Glutamate actions via NMDA receptors mediate a diverse range of physiological processes including synaptic transmission, cell survival gene regulation, long-term potentiation, and excitotoxicity (32, 33). Thus, increased release of glutamate during hypoxic conditions and parallel increases in oxidative stress may have important implications for cell survival. The lipid peroxidation product 4-hydroxy-2,3,-nonenal has been shown to directly modulate NMDA channel activity, causing increases in NMDA-induced intracellular calcium ion levels as well as being associated with increased phosphorylation of the NR1 receptor subunit, suggesting that such compounds may play a role in the pathological responses of neurons to oxidative stress by directly acting on glutamate receptors (34). This is consistent with the hypothesis of a vicious cycle in which NMDA receptor activation by glutamate leads to generation of reactive O2 species which, in turn, will enhance the release of glutamate as well as inhibit its reuptake and inactivation, ultimately leading to cellular death (35, 36). Murata and colleagues (37) have recently demonstrated that administration of the NMDA receptor antagonist MK-801 in conjunction with a free radical scavenger attenuated the neurotoxicity associated with hypoxia/reoxygenation even when treatment was administered during reoxygenation, suggesting that the combination of increased glutamate release and free radical production that occurs with reoxygenation may be responsible for the observed neuronal damage. Extrapolation of this concept to our rodent model of sleep apnea is supported by the observations that the magnitude of the hypoxic exposure is insufficient to induce marked increases in neuronal apoptosis when administered as a sustained paradigm. In contrast, substantial increases in programmed cell death and gliosis develop when the hypoxic exposure is administered in a cyclical fashion (7). Thus, it seems that the intermittent nature of the hypoxic stimulus, rather than the level of hypoxia per se, may trigger a differential array of tissue responses that underlie the observed cellular damage and subsequent behavioral impairments. We postulate that the cellular damage in response to IH likely involves a number of interrelated pathways, namely mitochondrial dysfunction, excitoxicity, oxidative stress, protein nitrosation and nitrosylation, and altered regulation of pro- and antiapoptotic gene cascades. The repeated reoxygenations that occur in IH may serve to deplete or compromise the innate defense mechanisms of the cell while failing to appropriately recruit inducible defense processes, ultimately resulting in increased vulnerability and apoptosis within sensitive brain regions. Evidence to this effect has been recently uncovered in our laboratory, whereby using proteomic approaches, multiple proteins associated with metabolic pathways, molecular chaperones, and apoptosis-related signaling cascades are differentially regulated in a highly IH-sensitive region of the hippocampus such as CA1 when compared with the more tolerant CA3 region (38).

PNU-101033E is a member of a novel group of antioxidant compounds, the pyrrolopyrimidines, that have been shown to significantly attenuate lipid peroxidation in the rat (39, 40). Due to their lack of a lipophilic steroid moiety, pyrrolopyrimidines are able to cross the blood–brain barrier and are therefore more likely to affect the delayed neuronal damage in the selectively vulnerable CA1 region of the hippocampus than antioxidant compounds that act primarily on the central nervous system microvascular endothelium, such as the 21-aminosteroid (lazaroid), tirilizad (41). In addition, pyrrolopyrimidines have been shown to be more potent and efficacious than other antioxidants with neuroprotective properties that are blood–brain barrier permeable (40, 41). Pyrrolopyrimidines, such as PNU-101033E, have been proposed to exert their antioxidant effects by reacting with radical species in which the pyrrolidine nitrogen quenches the radical species via the transfer of an electron. This reaction transforms the pyrrolopyrimidine into a radical cation, which can then react, i.e., trap, a second radical species (40, 41). Although inhibition of lipid peroxidation remains the most likely mechanism of action, it is important to note that PNU-101033E, similar to the spin-trap {alpha}-phenyl-N-tert-butlynitrone, has been shown to have neuroprotective effects even when given hours after an ischemic episode, leading to the suggestion that the neuroprotective effects of some classes of antioxidants may involve additional mechanisms, such as potentiating antiapoptotic mechanisms, which are distinct from those involving quenching of reactive O2 species (40, 42). Of note, however, the efficacy of the pyrrolopyrimidines in the protection of hippocampal CA1 neurons from delayed neuronal injury after hypoxia/ischemia is greatest when administered before reperfusion, and the efficacy declines as a function of the temporal delay in administration after reperfusion, suggesting that the major effects of this class of compounds result from inhibition of injury-associated lipid peroxidation (41).

In summary, although in addition to oxidant stress, there is a high probability that multiple other pathophysiological mechanisms may be involved, and effective reductions in the degree of oxidative stress within neural tissue exposed to IH using an electron spin trapper are associated with significant protection against the neurocognitive deficits induced by this exposure paradigm. Collectively, these findings provide initial evidence to support the use of antioxidant strategies in preventing end-organ injury in patients with sleep apnea.


   Acknowledgments
 
The authors are grateful to Pharmacia Corporation for kindly providing the compound PNU-101033E.


   FOOTNOTES
 
Supported by National Institutes of Health grants HL69932, HL63912, and HL66358, American Heart Association grant AHA-0050442N, and The Commonwealth of Kentucky Research Challenge Trust Fund. B.W.R. is supported by F32 HD42395 from National Institutes of Health.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form September 15, 2002; accepted in final form February 19, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Wiegand L, Zwillich CW. Obstructive sleep apnea. Dis Mon 1994;40:197–252.[Medline]
  2. Redline S, Strohl KP. Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Clin Chest Med 1998;19:1–19.[CrossRef][Medline]
  3. Gozal D. Morbidity of obstructive sleep apnea in children: facts and theory. Sleep Breath 2001;5:35–42.[CrossRef][Medline]
  4. Sleep apnea: is your patient at risk? National Heart, Lung, and Blood Institute Working Group on Sleep Apnea. Am Fam Physician 1996;53:247–253.[Medline]
  5. Adams N, Strauss M, Schluchter M, Redline S. Relation of measures of sleep-disordered breathing to neuropsychological functioning. Am J Respir Crit Care Med 2001;163:1626–1631.[Abstract/Free Full Text]
  6. Row BW, Kheirandish L, Neville JJ, Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr Res 2002;52:449–453.[CrossRef][Medline]
  7. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 2001;21:2442–2450.[Abstract/Free Full Text]
  8. Gozal E, Row BW, Schurr A, Gozal D. Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat. Neurosci Lett 2001;305:197–201.[CrossRef][Medline]
  9. Kadar T, Dachir S, Shukitt-Hale B, Levy A. Sub-regional hippocampal vulnerability in various animal models leading to cognitive dysfunction. J Neural Transm 1998;105:987–1004.[CrossRef][Medline]
  10. Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995;38:357–366.[CrossRef][Medline]
  11. Kohmura E, Yamada K, Hayakawa T, Kinoshita A, Matsumoto K, Mogami H. Hippocampal neurons become more vulnerable to glutamate after subcritical hypoxia: an in vitro study. J Cereb Blood Flow Metab 1990;10:877–884.[Medline]
  12. Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 1997;68:255–264.[Medline]
  13. Nicolle MM, Gonzalez J, Sugaya K, Baskerville KA, Bryan D, Lund K, Gallagher M, McKinney M. Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 2001;107:415–431.[CrossRef][Medline]
  14. Nicholls D, Attwell D. The release and uptake of excitatory amino acids. Trends Pharmacol Sci 1990;11:462–468.[CrossRef][Medline]
  15. Horakova L, Stolc S, Chromikova Z, Pekarova A, Derkova L. Mechanisms of hippocampal reoxygenation injury. Mol Chem Neuropathol 1998;33:223–236.[Medline]
  16. Katsura K, Rodriguez de Turco EB, Folbergrova J, Bazan NG, Siesjo BK. Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemia. J Neurochem 1993;61:1677–1684.[CrossRef][Medline]
  17. Siesjo BK, Rehncrona S, Smith D. Neuronal cell damage in the brain: possible involvement of oxidative mechanisms. Acta Physiol Scand Suppl 1980;492:121–128.
  18. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195–231.[CrossRef][Medline]
  19. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 1991;11:81–128.[CrossRef][Medline]
  20. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci 1999;19:1959–1964.[Abstract/Free Full Text]
  21. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11:1–16.[Medline]
  22. Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, Harper RK, Yan-Go FL, Harper RM. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382–1387.[Abstract/Free Full Text]
  23. Albin RL, Greenamyre JT. Alternative excitotoxic hypotheses. Neurology 1992;42:733–738.[Abstract/Free Full Text]
  24. Choi DW. Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 1996;6:667–672.[CrossRef][Medline]
  25. Schurr A, Payne RS, Heine MF, Rigor BM. Hypoxia, excitotoxicity, and neuroprotection in the hippocampal slice preparation. J Neurosci Methods 1995;59:129–138.[CrossRef][Medline]
  26. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann Neurol 1986;19:105–111.[CrossRef][Medline]
  27. Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. J Mol Med 2000;78:3–13.[CrossRef][Medline]
  28. Gozal E, Sachleben Jr LR, Guo SZ, Gozal D. Differential NMDA glutamate receptor changes following sustained or intermittent hypoxia in the rat brain. Sleep 2002;25:A333.
  29. Pichiule P, Chavez JC, Boero J, Arregui A. Chronic hypoxia induces modification of the N-methyl-D-aspartate receptor in rat brain. Neurosci Lett 1996;218:83–86.[CrossRef][Medline]
  30. Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 1998;54:369–415.[CrossRef][Medline]
  31. Said SI, Pakbaz H, Berisha HI, Raza S. NMDA receptor activation: critical role in oxidant tissue injury. Free Radic Biol Med 2000;28:1300–1302.[CrossRef][Medline]
  32. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002;5:405–414.[Medline]
  33. Greenamyre JT. The role of glutamate in neurotransmission and in neurologic disease. Arch Neurol 1986;43:1058–1063.[Abstract]
  34. Lu C, Chan SL, Haughey N, Lee WT, Mattson MP. Selective and biphasic effect of the membrane lipid peroxidation product 4-hydroxy-2,3-nonenal on N-methyl-D-aspartate channels. J Neurochem 2001;78:577–589.[CrossRef][Medline]
  35. Barth A, Barth L, Newell DW. Combination therapy with MK-801 and alpha-phenyl-tert-butyl-nitrone enhances protection against ischemic neuronal damage in organotypic hippocampal slice cultures. Exp Neurol 1996;141:330–336.[CrossRef][Medline]
  36. Pellegrini-Giampietro DE, Pulsinelli WA, Zukin RS. NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: effect of NMDA and non-NMDA receptor antagonists. J Neurochem 1994;62:1067–1073.[Medline]
  37. Murata T, Omata N, Fujibayashi Y, Waki A, Sadato N, Yoshimoto M, Wada Y, Yonekura Y. Posthypoxic reoxygenation-induced neurotoxicity prevented by free radical scavenger and NMDA/non-NMDA antagonist in tandem as revealed by dynamic changes in glucose metabolism with positron autoradiography. Exp Neurol 2000;164:269–279.[Medline]
  38. Gozal E, Gozal D, Pierce WM, Thongbeonkerd V, Scherzer JA, Sachleben LR Jr, Guo SZ, Cai J, Klein JB. Proteomic analysis of CA1 and CA3 regions of rat hippocampus and differential susceptibility to intermittent hypoxia. J Neurochem 2002;83:331–345.[CrossRef][Medline]
  39. Oostveen JA, Dunn E, Carter DB, Hall ED. Neuroprotective efficacy and mechanisms of novel pyrrolopyrimidine lipid peroxidation inhibitors in the gerbil forebrain ischemia model. J Cereb Blood Flow Metab 1998;18:539–547.[CrossRef][Medline]
  40. Hall ED, Andrus PK, Smith SL, Fleck TJ, Scherch HM, Lutzke BS, Sawada GA, Althaus JS, Vonvoigtlander PF, Padbury GE, et al. Pyrrolopyrimidines: novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models. J Pharmacol Exp Ther 1997;281:895–904.[Abstract/Free Full Text]
  41. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, Plesnila N, Baethmann A, Reulen HJ. Superior neuroprotective efficacy of a novel antioxidant (PNU-101033E) with improved blood-brain barrier permeability in focal cerebral ischemia. Stroke 1997;28:2018–2024.[Abstract/Free Full Text]
  42. Kelicen P, Cantuti-Castelvetri I, Pekiner C, Paulson KE. The spin trapping agent PBN stimulates H2 O2-induced Erk and Src kinase activity in human neuroblastoma cells. Neuroreport 2002;13:1057–1061.[Medline]



This article has been cited by other articles:


Home page
 Eur Respir JHome page
P. Levy, J-L. Pepin, C. Arnaud, R. Tamisier, J-C. Borel, M. Dematteis, D. Godin-Ribuot, and C. Ribuot
Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives
Eur. Respir. J., October 1, 2008; 32(4): 1082 - 1095.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. E. Jung, J. W. Simpkins, A. M. Wilson, H. F. Downey, and R. T. Mallet
Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats
J Appl Physiol, August 1, 2008; 105(2): 510 - 517.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
G. K. Soukhova-O'Hare, R. V. Ortines, Y. Gu, A. D. Nozdrachev, S. D. Prabhu, and D. Gozal
Postnatal Intermittent Hypoxia and Developmental Programming of Hypertension in Spontaneously Hypertensive Rats: The Role of Reactive Oxygen Species and L-Ca2+ Channels
Hypertension, July 1, 2008; 52(1): 156 - 162.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
I. C. Burckhardt, D. Gozal, E. Dayyat, Y. Cheng, R. C. Li, A. D. Goldbart, and B. W. Row
Green Tea Catechin Polyphenols Attenuate Behavioral and Oxidative Responses to Intermittent Hypoxia
Am. J. Respir. Crit. Care Med., May 15, 2008; 177(10): 1135 - 1141.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
O. S. Capdevila, L. Kheirandish-Gozal, E. Dayyat, and D. Gozal
Pediatric Obstructive Sleep Apnea: Complications, Management, and Long-term Outcomes
Proceedings of the ATS, February 15, 2008; 5(2): 274 - 282.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. Gozal and L. Kheirandish-Gozal
Cardiovascular Morbidity in Obstructive Sleep Apnea: Oxidative Stress, Inflammation, and Much More
Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 369 - 375.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
T. Yokoe, L. C. Alonso, L. C. Romano, T. C. Rosa, Robert. M. O'Doherty, A. Garcia-Ocana, K. Minoguchi, and C. P. O'Donnell
Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic {beta}-cell replication in mice
J. Physiol., February 1, 2008; 586(3): 899 - 911.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Gu, M. Lin, J. Liu, D. Gozal, K. E. Scrogin, R. Wurster, M. W. Chapleau, X. Ma, and Z. Cheng
Selective impairment of central mediation of baroreflex in anesthetized young adult Fischer 344 rats after chronic intermittent hypoxia
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2809 - H2818.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. M. Troncoso Brindeiro, A. Q. da Silva, K. J. Allahdadi, V. Youngblood, and N. L. Kanagy
Reactive oxygen species contribute to sleep apnea-induced hypertension in rats
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2971 - H2976.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
D. Gozal, O. S. Capdevila, L. Kheirandish-Gozal, and V. M. Crabtree
APOE {varepsilon}4 allele, cognitive dysfunction, and obstructive sleep apnea in children
Neurology, July 17, 2007; 69(3): 243 - 249.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. Gozal, V. M. Crabtree, O. Sans Capdevila, L. A. Witcher, and L. Kheirandish-Gozal
C-reactive Protein, Obstructive Sleep Apnea, and Cognitive Dysfunction in School-aged Children
Am. J. Respir. Crit. Care Med., July 15, 2007; 176(2): 188 - 193.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
K. J. S. Griffioen, H. W. Kamendi, C. J. Gorini, E. Bouairi, and D. Mendelowitz
Reactive Oxygen Species Mediate Central Cardiorespiratory Network Responses to Acute Intermittent Hypoxia
J Neurophysiol, March 1, 2007; 97(3): 2059 - 2066.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
V. Y. Polotsky and C. P. O'Donnell
Genomics of Sleep-disordered Breathing
Proceedings of the ATS, January 1, 2007; 4(1): 121 - 126.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. I. Pack
Advances in Sleep-disordered Breathing
Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 7 - 15.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
L. Chen, E. Einbinder, Q. Zhang, J. Hasday, C. W. Balke, and S. M. Scharf
Oxidative Stress and Left Ventricular Function with Chronic Intermittent Hypoxia in Rats
Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 915 - 920.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. Gozal and L. Kheirandish
Sleepiness and Neurodegeneration in Sleep-disordered Breathing: Convergence of Signaling Cascades
Am. J. Respir. Crit. Care Med., June 15, 2005; 171(12): 1325 - 1327.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. J. Thomas, B. R. Rosen, C. E. Stern, J. W. Weiss, and K. K. Kwong
Functional imaging of working memory in obstructive sleep-disordered breathing
J Appl Physiol, June 1, 2005; 98(6): 2226 - 2234.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
F. J. Golder and G. S. Mitchell
Spinal Synaptic Enhancement with Acute Intermittent Hypoxia Improves Respiratory Function after Chronic Cervical Spinal Cord Injury
J. Neurosci., March 16, 2005; 25(11): 2925 - 2932.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
E. Gozal, L. R. Sachleben Jr., M. J. Rane, C. Vega, and D. Gozal
Mild sustained and intermittent hypoxia induce apoptosis in PC-12 cells via different mechanisms
Am J Physiol Cell Physiol, March 1, 2005; 288(3): C535 - C542.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
H. E. Montgomery-Downs, V. M. Crabtree, and D. Gozal
Cognition, sleep and respiration in at-risk children treated for obstructive sleep apnoea
Eur. Respir. J., February 1, 2005; 25(2): 336 - 342.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. L. Feldman and W. A. Janczewski
Slip of the Tongue
Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 581 - 582.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. C. Veasey, G. Zhan, P. Fenik, and D. Pratico
Long-Term Intermittent Hypoxia: Reduced Excitatory Hypoglossal Nerve Output
Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 665 - 672.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. Sforza, J. Haba-Rubio, F. De Bilbao, T. Rochat, and V. Ibanez
Performance vigilance task and sleepiness in patients with sleep-disordered breathing
Eur. Respir. J., August 1, 2004; 24(2): 279 - 285.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 254 - 264.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 277 - 287.
[Full Text] [PDF]

Home page
 HypertensionHome page
A. S. Hui, J. B. Striet, G. Gudelsky, G. K. Soukhova, E. Gozal, D. Beitner-Johnson, S.-Z. Guo, L. R. Sachleben Jr, J. W. Haycock, D. Gozal, et al.
Regulation of Catecholamines by Sustained and Intermittent Hypoxia in Neuroendocrine Cells and Sympathetic Neurons
Hypertension, December 1, 2003; 42(6): 1130 - 1136.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200209-1050OCv1
167/11/1548    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow