Liang Dong, Li Guowei, Liao Xingzhi, Yu Dawei, Wu Jing, Zhang Mingqiang
Department of Emergency, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, 999 Xiwang Road, Jiading District, Shanghai 201801, PR China.
Department of Anesthesia, The 101st Hospital of PLA, Wuxi 214044, PR China.
Behav Brain Res. 2016 Jan 1;296:134-140. doi: 10.1016/j.bbr.2015.08.033. Epub 2015 Aug 28.
Sleep apnea is more frequently experienced in neonatal life. Here we investigated the causal contribution of NOX2-derived oxidative stress in the prefrontal cortex (PFC) to neurodevelopmental alterations and psychiatric anxiety in a neonatal rat model of sleep apnea. Neonatal postnatal day 5 (P5) rats were exposed to long-term intermittent hypoxia (LTIH) or room air (RA) for 10 days. In the PFC, we determined the impact (I) of LTIH exposures on NADPH oxidase-2 (NOX2) expression and oxidative stress (II) of pharmacological NOX2 inhibition on LTIH-induced neurodevelopmental alterations in the P14 and P49 rats. Endpoints were NOX2-derived oxidative stress, parvalbumin (PV)-positive cells (PV-cells) and psychiatric anxiety. The results showed neonatal LTIH exposures increased NOX2 expression in the PFC of P14 rats, which was accompanied with elevation of NOX activity. Neonatal LTIH exposures increased oxidative stress in cortical PV-cells characterized by elevation of 8-hydroxy-20-deoxyguanosine (8-OHDG) level and reduced PV immunoreactivity, PV-cell counts in the PFC of P14 and P49 rats. Neonatal LTIH exposures increased psychiatric anxiety levels in the P49 rats. Pretreatment of neonatal rats before each neonatal LTIH exposure with the antioxidant/NOX inhibitor apocynin prevented the reduced PV immunoreactivity, PV-cells loss in the PFC and development of anxiety-like behavior. Our data suggest that NOX2-derived oxidative stress might be involved in the developmental loss of PV-cells in the PFC and development of psychiatric anxiety for neonatal rats exposed to LTIH.
睡眠呼吸暂停在新生儿期更为常见。在此，我们在睡眠呼吸暂停的新生大鼠模型中研究了前额叶皮质（PFC）中NOX2衍生的氧化应激对神经发育改变和精神性焦虑的因果作用。出生后第5天（P5）的新生大鼠暴露于长期间歇性缺氧（LTIH）或室内空气（RA）中10天。在PFC中，我们确定了LTIH暴露对NADPH氧化酶-2（NOX2）表达的影响（I）以及药理学上抑制NOX2对P14和P49大鼠LTIH诱导的神经发育改变的影响（II）。研究终点为NOX2衍生的氧化应激、小白蛋白（PV）阳性细胞（PV细胞）和精神性焦虑。结果显示，新生大鼠LTIH暴露增加了P14大鼠PFC中NOX2的表达，并伴有NOX活性升高。新生大鼠LTIH暴露增加了皮质PV细胞中的氧化应激，其特征为8-羟基-2'-脱氧鸟苷（8-OHDG）水平升高、PV免疫反应性降低、P14和P49大鼠PFC中PV细胞数量减少。新生大鼠LTIH暴露增加了P49大鼠的精神性焦虑水平。在每次新生大鼠LTIH暴露前用抗氧化剂/NOX抑制剂夹竹桃麻素进行预处理，可预防PFC中PV免疫反应性降低、PV细胞丢失以及焦虑样行为的发展。我们的数据表明，NOX2衍生的氧化应激可能参与了暴露于LTIH的新生大鼠PFC中PV细胞的发育性丢失和精神性焦虑的发展。
