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维生素A与视黄酸联合使用可减轻成年小鼠新生儿高氧诱导的神经行为损伤。

Vitamin A and retinoic acid combination attenuates neonatal hyperoxia-induced neurobehavioral impairment in adult mice.

作者信息

Ramani Manimaran, van Groen Thomas, Kadish Inga, Ambalavanan Namasivayam, McMahon Lori L

机构信息

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, United States.

Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, United States.

出版信息

Neurobiol Learn Mem. 2017 May;141:209-216. doi: 10.1016/j.nlm.2017.04.013. Epub 2017 Apr 27.

Abstract

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well.

摘要

暴露于超生理水平氧气的早产儿,其执行功能和记忆功能往往较差,且在日后生活中与海马体体积减小有关。我们最近发现,新生期暴露于高氧环境的成年小鼠存在空间导航缺陷,探索行为增加,且与海马体萎缩有关。类视黄醇可减轻动物模型中高氧诱导的肺损伤,并降低早产儿的新生儿慢性肺病发生率。我们假设,在新生期高氧环境下给小鼠施用类视黄醇(维生素A+视黄酸[VARA]的组合),在成年后进行评估时,将减轻氧气诱导的认知障碍。将C57BL/6小鼠幼崽从出生后第2天至第14天暴露于高氧(85%氧气)或空气(21%氧气)环境中,并分别给予VARA或菜籽油(载体),然后再置于空气中。进行了神经行为学测试(莫里斯水迷宫、旷场和零迷宫测试)、结构评估(MRI和组织学)以及海马体蛋白测量。新生期高氧导致成年小鼠出现空间导航缺陷、探索行为增加,并伴有海马体萎缩,而施用VARA可减轻所有这些情况。在高氧环境下,与常氧相比,VARA在更大程度上增加了海马体中磷酸化和总雷帕霉素哺乳动物靶点以及突触素水平。总之,VARA减轻了新生期高氧诱导的成年小鼠神经行为障碍及相关的海马体体积减小,可能是通过增加mTOR信号传导和突触密度实现的。这些新数据表明,类视黄醇可能对处于高损伤风险的极早产儿具有神经保护作用,并且在其他氧化应激模型中也可能有效。

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