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. 2017 May;5(9):e13258.
doi: 10.14814/phy2.13258.

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

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

Brina Snyder et al. Physiol Rep. 2017 May.

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.

Keywords: Entorhinal cortex; RVLM; hippocampus; solitary tract nucleus; substantia nigra.

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Figures

Figure 1
Figure 1
Plasma AOPP levels of animals exposed to CIH: 7 days exposure to CIH (n = 18) significantly increases circulating oxidative stress in male rats. *P ≤ 0.05.
Figure 2
Figure 2
Significantly elevated expression of 8‐OHdG was observed in brain regions associated with early‐stage neurodegenerative diseases following 7 days of CIH exposure. *P ≤ 0.05. (A) An elevation of oxidative stress in animals exposed to 7 days CIH is observed in SN and layer II of the ETC as compared to controls animals. (B) CIH increased oxidative stress in the SN and ETC layer II. Data presented as mean number of cells exhibiting 8‐OHdG immunoreactivity/section ± SEM. Scale bar = 100 μm.
Figure 3
Figure 3
Significantly elevated expression of 8‐OHdG was observed in brain regions associated with intermediate AD following 7 days of CIH exposure. *P ≤ 0.05. (A) An elevation of oxidative stress in animals exposed to 7 days CIH is observed in both the dentate gyrus and the CA1 regions of the hippocampus. (B) CIH increased oxidative stress in the CA1 and dentate gyrus (DG). Data presented as mean number of cells exhibiting 8‐OHdG immunoreactivity/section ± SEM. Scale bar = 100 μm.
Figure 4
Figure 4
CIH induces an increase in circulating M1 (IL‐6, TNFα, IFNγ, IL‐5) and M2 (IL‐4, IL‐10, IL‐13) inflammatory markers. Dotted line indicates normalized controls (normoxia = 13, CIH = 18). *P ≤ 0.05.
Figure 5
Figure 5
Region‐specific inflammatory responses to CIH are observed in the brain, resulting in a proinflammatory profile in the SN and ETC. An anti‐inflammatory profile is observed in the dorsal hippocampus. Dotted line indicates normalized controls. * indicates significant compared to control, # indicates significant difference within animal. (A) A significant elevation of M1 cytokines in the SN of animals exposed to CIH leads to a higher M1 cytokine profile than M2 profile in that brain region (normoxia = 12, CIH = 15). (B) An overall reduction in M1 and M2 cytokines is observed in the RVLM of animals exposed to CIH. No significant difference in the M1/M2 cytokine profile was observed in this region associated with late‐stage neurodegenerative diseases (normoxia = 13, CIH = 15). (C) M2 cytokines are significantly lower than M1 cytokines in the ETC of animals exposed to CIH, which elevates the M1 profile over the M2 profile (normoxia = 11, CIH = 9). (D) M1 cytokines are significantly lower than M2 cytokines in the HIPP following CIH (normoxia = 13, CIH = 15).

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