Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration.

Brina Snyder,Brent Shell,J Thomas Cunningham,Rebecca L Cunningham

doi:10.14814/phy2.13258

Brina Snyder, Brent Shell + Show 2 more

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https://doi.org/10.14814/phy2.13258

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Abstract

Sleep apnea is a common comorbidity of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Previous studies have shown an association between elevated oxidative stress and inflammation with severe sleep apnea. Elevated oxidative stress and inflammation are also hallmarks of neurodegenerative diseases. We show increased oxidative stress and inflammation in a manner consistent with early stages of neurodegenerative disease in an animal model of mild sleep apnea. Male rats were exposed to 7 days chronic intermittent hypoxia (CIH) for 8 h/day during the light period. Following CIH, plasma was collected and tested for circulating oxidative stress and inflammatory markers associated with proinflammatory M1 or anti‐inflammatory M2 profiles. Tissue punches from brain regions associated with different stages of neurodegenerative diseases (early stage: substantia nigra and entorhinal cortex; intermediate: hippocampus; late stage: rostral ventrolateral medulla and solitary tract nucleus) were also assayed for inflammatory markers. A subset of the samples was examined for 8‐hydroxydeoxyguanosine (8‐OHdG) expression, a marker of oxidative stress‐induced DNA damage. Our results showed increased circulating oxidative stress and inflammation. Furthermore, brain regions associated with early‐stage (but not late‐stage) AD and PD expressed oxidative stress and inflammatory profiles consistent with reported observations in preclinical neurodegenerative disease populations. These results suggest mild CIH induces key features that are characteristic of early‐stage neurodegenerative diseases and may be an effective model to investigate mechanisms contributing to oxidative stress and inflammation in those brain regions.

Highlights

Sleep apnea is a comorbidity of several neurodegenerative diseases, such as Alzheimer’s disease (AD) (Beebe and Gozal 2002; Gagnon et al 2014; Troussiere et al 2014) and Parkinson’s disease (PD) (Arnulf et al 2002)
These results show that mild chronic intermittent hypoxia (CIH) increases systemic oxidative stress, consistent with the elevation in oxidative stress observed in patients with neurodegenerative diseases (Dai et al 2014)
CIH was associated with significant oxidative stress-mediated DNA damage in the substantia nigra (SN), layer II of the entorhinal cortex (ETC), and dorsal hippocampus, brain regions linked with PD and AD, respectively (Figs. 2A and 3A)

Summary

Introduction

Sleep apnea is a comorbidity of several neurodegenerative diseases, such as Alzheimer’s disease (AD) (Beebe and Gozal 2002; Gagnon et al 2014; Troussiere et al 2014) and Parkinson’s disease (PD) (Arnulf et al 2002). In patients with PD who suffer from sleep disordered breathing, the severity of sleep apnea corresponds with the severity of PD (Diederich et al 2005). This suggests sleep apnea may contribute to the risk of neurodegeneration. Sleep apnea is a common disorder resulting in interruptions in breathing that cause alternating periods of reduced oxygen inspiration (apnea or hypopnea) followed by rapid reoxygenation while a patient sleeps (Dempsey et al 2010). The periodic rapid reoxygenation events may contribute to the pathogenesis of sleep apnea (Kaczmarek et al 2013; Boroujerdi and Milner 2015)

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