Golan M Hava, Mane Revital, Molczadzki Gabriela, Zuckerman Michal, Kaplan-Louson Vered, Huleihel Mahmoud, Perez-Polo J Regino
Department of Developmental Molecular Genetics, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
Neuropharmacology. 2009 Oct-Nov;57(5-6):511-22. doi: 10.1016/j.neuropharm.2009.07.028. Epub 2009 Jul 25.
Prenatal hypoxia ischemia is a major cause of neurodevelopmental impairment in the newborn, associated with risk for motor, behavioral and cognitive impaired outcomes. We used an established mouse model of maternal hypoxia to examine the immediate molecular responses of signaling pathways associated with both cell death and neurogenesis. We also characterized responses to maternal pre-treatment with MgSO(4). Maternal hypoxia at embryonic day 17 (E17) failed to trigger inflammation or cell death in fetal brain at 24 h after hypoxia. However, maternal hypoxia decreased levels of neuronal migration signaling: Reelin (53% of control), Disabled 1 (Dab1, 77% of control), and amyloid precursor protein (APP, 64% of control) 2 h after the insult. These changes persisted for 24 h. At later times, Reelin levels in hippocampi of newborns in the maternal hypoxia-treated group increased compared to controls. Full protection from maternal hypoxia effects on hippocampal Reelin levels resulted from maternal pre-treatment with MgSO(4). Hypoxia and MgSO(4) increased radial and lateral migration distance in the CA1 four days after the insult, while in the DG the hypoxia treatment alone increased migration. Maternal hypoxia and MgSO(4) pre-treatment also stimulated hippocampal expression of genes related to neurogenesis, such as BDNF and NeuroD4. Taken together, the long-term neurodevelopmental outcome of prenatal and perinatal hypoxia may depend on perturbation of developmental signals that affect neuronal migration.
产前缺氧缺血是新生儿神经发育障碍的主要原因，与运动、行为和认知受损结局的风险相关。我们使用已建立的母体缺氧小鼠模型来研究与细胞死亡和神经发生相关的信号通路的即时分子反应。我们还对母体用硫酸镁预处理后的反应进行了表征。胚胎第17天（E17）的母体缺氧在缺氧后24小时未能触发胎儿大脑中的炎症或细胞死亡。然而，母体缺氧在损伤后2小时降低了神经元迁移信号的水平：Reelin（对照组的53%）、Disabled 1（Dab1，对照组的77%）和淀粉样前体蛋白（APP，对照组的64%）。这些变化持续了24小时。在随后的时间里，母体缺氧治疗组新生儿海马体中的Reelin水平与对照组相比有所增加。母体用硫酸镁预处理可完全保护母体缺氧对海马体Reelin水平的影响。缺氧和硫酸镁在损伤后四天增加了CA1区的径向和横向迁移距离，而在齿状回中，仅缺氧治疗就增加了迁移。母体缺氧和硫酸镁预处理还刺激了与神经发生相关的基因如脑源性神经营养因子（BDNF）和NeuroD4在海马体中的表达。综上所述，产前和围产期缺氧的长期神经发育结局可能取决于影响神经元迁移的发育信号的扰动。
