Nair Deepti, Ramesh Vijay, Gozal David
Section of Sleep Medicine, Biological Sciences Division, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States.
Atlantic Health System, Morristown, NJ, United States.
Front Neurol. 2018 Jun 5;9:426. doi: 10.3389/fneur.2018.00426. eCollection 2018.
Obstructive sleep apnea (OSA) is a highly prevalent disease manifesting as intermittent hypoxia during sleep (IH) and is increasingly recognized as being independently associated with neurobehavioral deficits. These deficits may be due to increased apoptosis in the hippocampus and cerebral cortex, as well as increased oxidative stress and inflammation. It has been reported that neuroglobin (Ngb) is upregulated in response to hypoxia-ischemia insults and exhibits a protective role in ischemia-reperfusion brain injury. We hypothesized that transgenic overexpression of Ngb would attenuate spatial learning deficits in a murine model of OSA. Wild-type mice and Ngb overexpressing male mice (Ngb-TG) were randomly assigned to either IH or room air (RA) exposures. The effects of IH during the light period on performance in a water maze spatial task were assessed, as well as anxiety and depressive-like behaviors using elevated plus maze (EPM) and forced swim tests. Cortical tissues from all the mice were extracted for biochemical studies for lipid peroxidation. Ngb TG mice exhibited increased Ngb immunoreactivity in brain tissues and IH did not elicit significant changes in Ngb expression in either Ngb-TG mice or WT mice. On a standard place training task in the water maze, Ngb-TG mice displayed preserved spatial learning, and were protected from the reduced spatial learning performances observed in WT mice exposed to IH. Furthermore, anxiety and depression levels were enhanced in WT mice exposed to IH as compared to RA controls, while alterations emerged in Ngb-TG mice exposed to IH. Furthermore, WT mice, but not Ngb-TG mice had significantly elevated levels of malondialdehyde in cortical lysates following IH exposures. In a murine model of OSA, oxidative stress responses and neurocognitive and behavioral impairments induced by IH during sleep are attenuated by the neuroprotective effects of Ngb.
阻塞性睡眠呼吸暂停（OSA）是一种高度流行的疾病，表现为睡眠期间间歇性缺氧（IH），并且越来越被认为与神经行为缺陷独立相关。这些缺陷可能是由于海马体和大脑皮层中细胞凋亡增加，以及氧化应激和炎症增加所致。据报道，神经球蛋白（Ngb）在缺氧缺血性损伤反应中上调，并在缺血再灌注脑损伤中发挥保护作用。我们假设Ngb的转基因过表达将减轻OSA小鼠模型中的空间学习缺陷。将野生型小鼠和Ngb过表达雄性小鼠（Ngb-TG）随机分配至IH或常氧（RA）暴露组。评估了光照期IH对水迷宫空间任务表现的影响，以及使用高架十字迷宫（EPM）和强迫游泳试验评估焦虑和抑郁样行为。提取所有小鼠的皮质组织用于脂质过氧化的生化研究。Ngb TG小鼠脑组织中Ngb免疫反应性增加，并且IH在Ngb-TG小鼠或野生型小鼠中均未引起Ngb表达的显著变化。在水迷宫的标准位置训练任务中，Ngb-TG小鼠表现出保留的空间学习能力，并且免受暴露于IH的野生型小鼠中观察到的空间学习能力下降的影响。此外，与RA对照组相比，暴露于IH的野生型小鼠的焦虑和抑郁水平升高，而暴露于IH的Ngb-TG小鼠出现了改变。此外，暴露于IH后，野生型小鼠而非Ngb-TG小鼠的皮质裂解物中丙二醛水平显著升高。在OSA小鼠模型中，睡眠期间IH诱导的氧化应激反应以及神经认知和行为损伤通过Ngb的神经保护作用而减弱。
