Abstract
BackgroundEpisodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH). Our aim was to investigate the effects of IH on cerebellar granule cells and to identify the mechanism of IH-induced cell death.MethodsCerebellar granule cells were freshly prepared from neonatal Sprague-Dawley rats. IH was created by culturing the cerebellar granule cells in the incubators with oscillating O2 concentration at 20% and 5% every 30 min for 1-4 days. The results of this study are based on image analysis using a confocal microscope and associated software. Cellular oxidative stress increased with increase in IH. In addition, the occurrence of cell death (apoptosis and necrosis) increased as the duration of IH increased, but decreased in the presence of an iron chelator (phenanthroline) or poly (ADP-ribose) polymerase (PARP) inhibitors [3-aminobenzamide (3-AB) and DPQ]. The fluorescence of caspase-3 remained the same regardless of the duration of IH, and Western blots did not detect activation of caspase-3. However, IH increased the ratio of apoptosis-inducing factor (AIF) translocation to the nucleus, while PARP inhibitors (3-AB) reduced this ratio.ResultsAccording to our findings, IH increased oxidative stress and subsequently leading to cell death. This effect was at least partially mediated by PARP activation, resulting in ATP depletion, calpain activation leading to AIF translocation to the nucleus.ConclusionsWe suggest that IH induces cell death in rat primary cerebellar granule cells by stimulating oxidative stress PARP-mediated calpain and AIF activation.
Highlights
Episodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH)
We suggest that IH induces cell death in rat primary cerebellar granule cells by stimulating oxidative stress poly (ADP-ribose) polymerase (PARP)-mediated calpain and apoptosis-inducing factor (AIF) activation
This study evaluates the effects of IH-induced oxidative stress on cell death, as well as the cell death pathways involved in these processes, in primary rat cerebellar granule cell cultures
Summary
Episodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH). Patients with OSA are at increased risk of cardiovascular diseases and neuro-cognitive deficits [3,4]. Magnetic resonance imaging studies in OSA patients have revealed significant reductions in gray matter of several brain regions, including the cortex, hippocampus, and cerebellum [5]. Episodic cessation of airflow during sleep in patients with OSA results in intermittent hypoxia (IH) [1], which cycles through periods of hypoxia and reoxygenation. Reoxygenation increases the risk of oxidative stress and cell injury [6]. Oxidative stress results from the presence of excessive reactive oxygen species (ROS), including superoxide (O2-·), hydrogen peroxide (H2O2), and the hydroxyl radical (OH ·). Excessive ROS is associated with aging, cardiovascular disease, and neuronal diseases
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