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

Abstract

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.

Figure 1. The molecular findings for glutathione reductase-1 and glyoxalase-1 levels. A) Western blots from three nervous system areas showing the expression of glyoxalase-1, glutathione reductase-1, and the structural protein beta-actin used as a control between groups. B) Glyoxalase-1 levels in the hippocampus, cerebral cortex, and striatum were similar between the hypoxia (n=13) and control groups (n=6); C) Glutathione reductase-1 levels were 42% higher in the cerebral cortex of animals exposed to intermittent hypoxia.