Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea.

In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction. IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates. The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.

在啮齿动物中，暴露于间歇性缺氧（IH）——阻塞性睡眠呼吸暂停（OSA）的一个标志——与神经行为损伤、海马体和皮质细胞凋亡增加以及氧化应激和炎症增加有关。在暴露于相似程度的持续性缺氧（SH）的啮齿动物中，这些发现明显减弱。对缺氧敏感的基因促红细胞生成素（EPO）已成为一种主要的内源性神经保护剂，并且可能参与IH诱导的神经元功能障碍。 IH仅诱导海马体中EPO mRNA的表达短暂增加，而在暴露于SH的小鼠中这种增加持续存在。IH（而非SH）对水迷宫中的两种空间学习形式产生不利影响，并增加了氧化应激标志物。然而，在标准的位置训练任务中，外源性给予EPO治疗的小鼠表现出正常的学习能力，并且免受暴露于IH的赋形剂处理（C）同窝小鼠中观察到的空间学习缺陷的影响。此外，与常氧环境相比，IH环境中的焦虑水平升高，而在EPO治疗的小鼠中焦虑没有变化。另外，C小鼠（而非EPO治疗的暴露于IH的小鼠）的NADPH氧化酶表达水平显著升高，并且皮质和海马体裂解物中的丙二醛（MDA）和8 - 羟基脱氧鸟苷（8 - OHDG）水平也升高。 睡眠期间IH诱导的氧化应激反应和神经行为损伤至少部分是由EPO表达与NADPH氧化酶活性增加之间的失衡介导的，因此针对中枢神经系统中EPO表达的药物可能为睡眠呼吸障碍提供一种治疗策略。