Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction

Abstract

Breathing-disordered states, such as in obstructive sleep apnea, which are cyclical in nature, have been postulated to induce neurocognitive morbidity in both pediatric and adult populations. The oscillatory nature of intermittent hypoxia, especially when chronic, may mimic the paradigm of ischemia-reperfusion in that tissues and cells are exposed to episodes of low and high O(2) and this may lead to oxidant stress. Therefore, we decided to explore the potential contribution of oxidant stress in our intermittent hypoxia/hypercapnia animal model and the role that mitochondria might play in this stress. Neonatal mice were exposed to intermittent hypoxia/hypercapnia for 10 days and 2 wk. Combined intermittent hypoxia/hypercapnia led to a marked increase in apoptotic cell death in the cerebral cortex. Oxygen consumption studies in isolated mitochondria from intermittent hypoxia/hypercapnia-exposed brains demonstrated significant reductions in both state 4 and state 3 respiratory activities by approximately 60% and 75%, respectively. Electron paramagnetic resonance spectroscopy registered a significant increase in superoxide production during nonphosphorylating state 4 by 37%, although superoxide leakage during state 3 did not increase upon treatment. Neuronal superoxide-specific dihydroethidium oxidation was also greater in exposed animals. These studies indicate that intermittent hypoxia/hypercapnia leads to oxidative stress due to mitochondrial response within the mouse central nervous system.

Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination

“…There are several reports exploring the role of experimental intermittent hypoxemia in neurologic morbidity associated with adult sleep apnea and apnea of prematurity (Cai et al, 2011(Cai et al, , 2012Douglas et al, 2010;Oorschot et al, 2013;Xu et al, 2004). Similar to our results, studies on neonatal animals demonstrated poorer WM myelination in mice and rats exposed to IH compared to their naïve controls.…”

“…In another report hypoxic exposure was relatively short (three days), but very severe (1.5% O 2 for 15 min, seven events a day) (Oorschot et al, 2013). This may explain a significant loss of precursors of myelin-producing cells observed in the above referenced model and hippocampal and cortical neuronal loss in the IH-models by Douglas et al (2010) and Gozal et al (2001). Furthermore, in the protocol reported by Cai et al (2012) IH stress resulted in bradycardia and the protocol by Oorschot et al (2013) was not controlled for changes in the CBF or the presence of bradycardia.…”

Effects of exercise and poor indoor air quality on learning, memory and blood IGF-1 in adolescent mice

“…These results indicate that the cortex may be affected more adversely than other regions of brain by poor IAQ. Also, it is known that apoptosis is increased by hypoxia/hypercapnia in the cerebral cortex (Douglas et al 2010).…”

Early Sleep Apnea Detection and Treatment in Stroke Rehabilitation

“…Apneas and hypopneas cause recurrent cerebral hypoxia that can lead to the production of neuroinhibitory peptides and increased apoptosis of cerebral neurons, both of which could further impair cerebral function [23,24]. Sleep disruption and excessive daytime sleepiness associated with OSA could also play a role in impairing attention and functional capacity in stroke rehabilitation.…”