Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea

Xu, Wei; Chi, Liying; Row, Barry W.; Xu, Raobo; Ke, Ya; Xu, Bao‐Hua; Luo, Chun; Kheirandish, Leila; Gozal, David; Liu, R

doi:10.1016/j.neuroscience.2004.03.055

Cited by 346 publications

(294 citation statements)

References 52 publications

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“…The finding of fasting hyperglycemia occurring in association with intermittent hypoxia is consis tent with previous reports (5,6). To the best of our knowledge, this is the first report of melatonin hav ing a role in preventing intermittent hypoxiarelated hyperglycemia.…”

Section: Discussionsupporting

confidence: 91%

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Melatonin prevents hyperglycemia in a model of sleep apnea

Kaminski

Martinez

Fagundes

et al. 2015

Arch. Endocrinol. Metab.

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Objective: Obstructive sleep apnea is a common disorder associated with aging and obesity. Apneas cause repeated arousals, intermittent hypoxia, and oxidative stress. Changes in glucolipidic profile occur in apnea patients, independently of obesity. Animal models of sleep apnea induce hyperglycemia. This study aims to evaluate the effect of the antioxidants melatonin and N-acetylcysteine on glucose, triglyceride, and cholesterol levels in animals exposed to intermittent hypoxia. Materials and methods: Two groups of Balb/c mice were exposed to intermittent hypoxia (n = 36) or sham intermittent hypoxia (n = 36) for 35 days. The intermittent hypoxia group underwent a total of 480 cycles of 30 seconds reducing the inspired oxygen fraction from 21% to 7 ± 1% followed by 30 seconds of normoxia, during 8 hours daily. Melatonin or N-acetylcysteine were injected intraperitonially daily from day 21 on. Results: At day 35, glucose levels were significantly higher in the intermittent hypoxia group than in the control group. The intermittent hypoxia groups receiving N-acetylcysteine and vehicle showed higher glucose levels than the group receiving melatonin. The lipid profile was not affected by intermittent hypoxia or antioxidant administration. Conclusions:The present results suggest that melatonin prevents the well-recognized increase in glucose levels that usually follows exposure to intermittent hypoxia. Further exploration of the role of melatonin in sleep apnea is warranted. Arch Endocrinol Metab. 2015;59(1):66-70

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Section: Discussionsupporting

confidence: 91%

“…The repeated hypoxic episodes seen in OSA in crease oxidative stress (5), which may represent a link between apneas and diabetes (6)(7)(8). Intermittent hy poxia, a mo del of OSA, induces acute insulin resistance in healthy humans (9) and animals (10).…”

Section: Introductionmentioning

confidence: 99%

Melatonin prevents hyperglycemia in a model of sleep apnea

Kaminski

Martinez

Fagundes

et al. 2015

Arch. Endocrinol. Metab.

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“…Thus, whereas cleaved caspase-3 is upregulated transiently in synaptic remodeling (Huesmann and Clayton, 2006), prolonged activation of caspase-3 is considered a marker of neural injury in models of ischemia, trauma, and neurodegeneration (Cohen, 1997;Springer, 2002;Rami, 2003). Additionally, cleaved caspase-3 has been identified in cortical neurons of animals exposed to LTIH (Xu et al, 2004) and thus may highlight injured wake-active neurons. The second and fifth 1:6 sets of sections from the above nonsleep-deprived mice (LTIH, n ϭ 5; sham LTIH, n ϭ 5) were used for double labeling of wake neuron identifier and cleaved caspase-3 (CC3) using polyclonal rabbit anti-cleaved caspase-3 primary antibody (1:500; Cell Signaling Technology, Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Zhu¹,

Fenik²,

Zhan³

et al. 2007

J. Neurosci.

165

117

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The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/ reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/ reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67 phox to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

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“…However, it is highly probable that oxidative stress plays a significant role (reviewed by WANG et al [27] ). Thus, it has been well established that there are increased expressions of oxidative stress markers found in the brains of rodents subjected to IH treatment [28][29][30] . Administration of antioxidants [28] or over-expressing superoxide dismutase [30] attenuated reactive oxygen species (ROS) production and apoptosis in chronic IH-treated animals.…”

Section: Reviewmentioning

confidence: 99%

“…Thus, it has been well established that there are increased expressions of oxidative stress markers found in the brains of rodents subjected to IH treatment [28][29][30] . Administration of antioxidants [28] or over-expressing superoxide dismutase [30] attenuated reactive oxygen species (ROS) production and apoptosis in chronic IH-treated animals. More recent evidence supports a specific role of NADPH oxidase in IH-induced oxidative stress [31,32] .…”

Section: Reviewmentioning

confidence: 99%

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Xie

Yung

2012

Acta Pharmacol Sin

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Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated.

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Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea

Cited by 346 publications

References 52 publications

Melatonin prevents hyperglycemia in a model of sleep apnea

Melatonin prevents hyperglycemia in a model of sleep apnea

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

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