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首页> 外文期刊>Brain research >CIH-induced neurocognitive impairments are associated with hippocampal Ca2+ overload, apoptosis, and dephosphorylation of ERK1/2 and CREB that are mediated by overactivation of NMDARs
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CIH-induced neurocognitive impairments are associated with hippocampal Ca2+ overload, apoptosis, and dephosphorylation of ERK1/2 and CREB that are mediated by overactivation of NMDARs

机译：CIH诱导的神经认知障碍与海马Ca2 +超负荷，细胞凋亡以及NMDAR过度激活介导的ERK1 / 2和CREB的去磷酸化有关

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Chronic intermittent hypoxia (CIH) is commonly seen in patients with obstructive sleep apnea, and has been hypothesized to underlie the neurocognitive dysfunction in these patients. However, its cellular and molecular mechanisms remain to be defined. The present study aimed to investigate, in a mouse CIH model, the role of NMDA receptor (NMDAR) activation in mediating the CIH-induced neurocognitive impairments, caspase expression and dysregulated Ca2+ signaling pathways in hippocampus. Male ICR mice (n=45) were exposed to CIH (8 h/day) or room air (control) for 4 weeks. After 4-week treatment, neurobehavioral assessments were performed by Morris water maze test, hippocampal [Ca2+]i was evaluated by flow cytometry; and protein expressions of caspase-3, caspase-9, PARP, p-ERK1/2 and p-CREB in hippocampus were measured by Western blotting. Our results showed that, compared to control animals, 4-week exposure to CIH produced significant spatial learning and memory impairments in CIH mice. Increased caspase expression in hippocampus was observed in OH mice associated with significant elevation of [Ca2+]i and dephosphorylation of ERK and CREB expression. When the NMDAR antagonist memantine was administered by intraperitoneal injection prior to daily exposure to CIH, at a sub-therapeutic dose of 5 mg/kg/day not shown to impact the neurobehavioral performance in control animals, the neurocognitive impairments as well as the neurobiochemical changes were abolished or normalized in the CIH mice. Our study suggests that overactivation of NMDARs and the Ca2+ overload-dependent ERK/CREB dysregulation is one of the important mechanisms in mediating the CIH-induced neurocognitive impairments. (C) 2015 Elsevier B.V. All rights reserved.
机译：慢性间歇性缺氧（CIH）在阻塞性睡眠呼吸暂停患者中很常见，并且被认为是这些患者神经认知功能障碍的基础。然而，其细胞和分子机制仍有待确定。本研究旨在调查小鼠CIH模型中NMDA受体（NMDAR）激活在介导CIH诱导的海马神经认知障碍，胱天蛋白酶表达和Ca2 +信号通路失调中的作用。将雄性ICR小鼠（n ＝ 45）暴露于CIH（8小时/天）或室内空气（对照）4周。治疗4周后，通过莫里斯水迷宫测试进行神经行为评估，通过流式细胞术评估海马[Ca2 +] i。 Western blotting检测海马caspase-3，caspase-9，PARP，p-ERK1 / 2和p-CREB的蛋白表达。我们的结果表明，与对照组动物相比，CIH暴露4周会在CIH小鼠中产生明显的空间学习和记忆障碍。在OH小鼠中观察到海马caspase表达增加，这与[Ca2 +] i的显着升高以及ERK和CREB表达的去磷酸化有关。在每天暴露于CIH之前通过腹膜内注射给予NMDAR拮抗剂美金刚时，亚治疗剂量为5 mg / kg /天，未显示出对对照动物的神经行为有影响，神经认知障碍以及神经生化变化在CIH小鼠中被废除或标准化。我们的研究表明，NMDARs的过度激活和Ca2 +超负荷依赖性ERK / CREB失调是介导CIH诱导的神经认知损害​​的重要机制之一。 （C）2015 Elsevier B.V.保留所有权利。

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