Intermittent hypoxia, brain glyoxalase-1 and glutathione reductase-1, and anxiety-like behavior in mice

Objective: Sleep apnea has been associated with anxiety, but the mechanisms of the sleep apnea-anxiety relationship are unresolved. Sleep apnea causes oxidative stress, which might enhance anxiety-like behavior in rodents. To clarify the apnea-anxiety connection, we tested the effect of intermittent hypoxia, a model of sleep apnea, on the anxiety behavior of mice. Methods: The rodents were exposed daily to 480 one-minute cycles of intermittent hypoxia to a nadir of 7±1% inspiratory oxygen fraction or to a sham procedure with room air. After 7 days, the mice from both groups were placed in an elevated plus maze and were video recorded for 10 min to allow analysis of latency, frequency, and duration in open and closed arms. Glyoxalase-1 (Glo1) and glutathione reductase-1 (GR1) were measured in the cerebral cortex, hippocampus, and striatum by Western blotting. Results: Compared to controls, the intermittent hypoxia group displayed less anxiety-like behavior, perceived by a statistically significant increase in the number of entries and total time spent in open arms. A higher expression of GR1 in the cortex was also observed. Conclusion: The lack of a clear anxiety response as an outcome of intermittent hypoxia exposure suggests the existence of additional layers in the anxiety mechanism in sleep apnea, possibly represented by sleepiness and irreversible neuronal damage.

Intermittent hypoxia, brain glyoxalase-1 and glutathione reductase-1, and anxiety-like behavior in mice.

OBJECTIVE: Sleep apnea has been associated with anxiety, but the mechanisms of the sleep apnea-anxiety relationship are unresolved. Sleep apnea causes oxidative stress, which might enhance anxiety-like behavior in rodents. To clarify the apnea-anxiety connection, we tested the effect of intermittent hypoxia, a model of sleep apnea, on the anxiety behavior of mice. METHODS: The rodents were exposed daily to 480 one-minute cycles of intermittent hypoxia to a nadir of 7±1% inspiratory oxygen fraction or to a sham procedure with room air. After 7 days, the mice from both groups were placed in an elevated plus maze and were video recorded for 10 min to allow analysis of latency, frequency, and duration in open and closed arms. Glyoxalase-1 (Glo1) and glutathione reductase-1 (GR1) were measured in the cerebral cortex, hippocampus, and striatum by Western blotting. RESULTS: Compared to controls, the intermittent hypoxia group displayed less anxiety-like behavior, perceived by a statistically significant increase in the number of entries and total time spent in open arms. A higher expression of GR1 in the cortex was also observed. CONCLUSION: The lack of a clear anxiety response as an outcome of intermittent hypoxia exposure suggests the existence of additional layers in the anxiety mechanism in sleep apnea, possibly represented by sleepiness and irreversible neuronal damage.

Exercise, Occupational Activity, and Risk of Sleep Apnea: A Cross-Sectional Study.

STUDY OBJECTIVES: To investigate whether structured exercise and occupational activity are associated with obstructive sleep apnea (OSA) severity. METHODS: The International Physical Activity Questionnaire was answered by 5,453 individuals who underwent full-night polysomnography. Participants were classified as exercisers or non-exercisers and also as occupationally active or non-active. The apnea-hypopnea index (AHI), minimum oxygen saturation (SaO2min), and time with saturation below 90% (TB90%) during polysomnography were used as indicators of OSA severity. RESULTS: The sample included mostly men (59%), non-exercisers (56%), and occupationally non-active individuals (75%). Mean age (± standard deviation) was 44 ± 14 years, and mean body mass index was 29.9 ± 7.3 kg/m2. Non-exercisers had higher AHI (median 14, 25-75% interquartile range 4-34) than exercisers (8 [2-24]), lower SaO2min (83 ± 9 vs. 86 ± 8%), and longer TB90% (2 [0-18] vs. 0 [0-7] minutes), with p < 0.001 for all comparisons. AHI was higher in active (16 [6-34]) vs. non-active occupations (10 [3-27]; p < 0.001). Multinomial logistic regression with control for age, sex, overweight, obesity, and occupational activity showed that structured exercise was significantly associated with a 23% lower odds ratio for moderate OSA and 34% lower odds ratio for severe OSA. Active occupation was not associated with OSA. CONCLUSIONS: Structured physical exercise is associated with lower odds for OSA, independently of confounders. Occupational activity does not seem to replace the effects of regular exercise. Compensatory behaviors may be involved in these diverging outcomes. Our results warrant further research about the effect of occupational activity on OSA severity.

Factors influencing the response of psychological symptoms to continuous positive airway pressure therapy.

PURPOSE: To examine whether in obstructive sleep apnea (OSA) patients the degree of sleepiness, slow-wave sleep (SWS) loss, and hypoxia influence the response of psychological symptoms to continuous positive airway pressure (CPAP) therapy. METHODS: A prospectively planned cohort was assessed. Participants underwent full overnight polysomnography. All answered the Symptom Checklist-90-Revised (SCL-90) and the Epworth sleepiness scale (ESS). Only cases with an apnea-hypopnea index ≤60 events/h were 24 invited to participate. In an interview by telephone, after a follow-up period between 2 months and 1 year, patients informed whether they were in treatment with CPAP or remained voluntarily untreated. Subjects who accepted to participate answered for the second time the SCL-90 and the ESS. The baseline variables of interest were: (a) score of the ESS, (b) duration of SWS, and (c) time with arterial oxygen saturation below 90%. The outcomes were the change in SCL-90 scores in all dimensions and indices of the questionnaire. RESULTS: A number of 73 patients, mostly men, were included. In uncontrolled analyses, CPAP-treated patients showed significant improvement at follow-up in 10 of the 13 SCL-90 scores. Comparing with the control group, only six scores were improved. Baseline sleepiness was the best predictor of SCL-90 improvement after CPAP treatment in the univariate analyses, and the only significant predictor of improvement in a multivariate regression model. CONCLUSIONS: Sleepiness may supersede other factors that influence psychological improvement in CPAP-treated patients with severe OSA.

Brown adipose tissue: is it affected by intermittent hypoxia?

BACKGROUND: Intermittent hypoxia (IH), a model of sleep apnea, produces weight loss in animals. We hypothesized that changes in brown adipose tissue (BAT) function are involved in such phenomenon. We investigated the effect of IH, during 35 days, on body weight, brown adipose tissue wet weight (BATww) and total protein concentration (TPC) of BAT. METHODS: We exposed Balb/c mice to 35 days of IH (n = 12) or sham intermittent hypoxia (SIH; n = 12), alternating 30 seconds of progressive hypoxia to a nadir of 6%, followed by 30 seconds of normoxia. During 8 hours, the rodents underwent a total of 480 cycles of hypoxia/reoxygenation, equivalent to an apnea index of 60/hour. BAT was dissected and weighed while wet. Protein was measured using the Lowry protein assay. RESULTS: Body weight was significantly reduced in animals exposed to IH, at day 35, from 24.4 ± 3.3 to 20.2 ± 2.2 g (p = 0.0004), while in the SIH group it increased from 23.3 ± 3.81 to 24.1 ± 2.96 g (p = 0.23). BATww was also lower in IH than in SIH group (p = 0.00003). TPC of BAT, however, was similar in IH (204.4 ± 44.3 µg/100 µL) and SIH groups (213.2 ± 78.7 µg/100 µL; p = 0.74) and correlated neither with body weight nor with BATww. TPC appeared to be unaffected by exposure to IH also in multivariate analysis, adjusting for body weight and BATww. The correlation between body weight and BATww is significant (rho= 0.63) for the whole sample. When IH and SIH groups are tested separately, the correlations are no longer significant (rho = 0.48 and 0.05, respectively). CONCLUSION: IH during 35 days in a mice model of sleep apnea causes weight loss, BATww reduction, and no change in TPC of BATww. The mechanisms of weight loss under IH demands further investigation.