Piscopo Paola, Bernardo Antonietta, Calamandrei Gemma, Venerosi Aldina, Valanzano Angela, Bianchi Daniela, Confaloni Annamaria, Minghetti Luisa
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161, Roma, Italy.
Exp Neurol. 2008 Jan;209(1):192-8. doi: 10.1016/j.expneurol.2007.09.014. Epub 2007 Oct 25.
Cyclooxygenase-2 (COX-2) and presenilin (PSEN) 1 and 2 genes are regulated during development as well as in pathological conditions associated to hypoxia. In this study, we investigated their patterns of expression during the first 2 weeks of postnatal life in a rat model of moderate global perinatal asphyxia that we have previously reported to be characterized by early oxidative stress and delayed behavioral alterations. In the hippocampus, global perinatal asphyxia induced an early up-regulation COX-2 mRNA (postnatal day, pnd, 1), which preceded those of PSEN 1 and 2 genes, observed at pnd 4. At pnd 11, the expression of all three genes was decreased compared to control animals. In addition, we analyzed the expression of the scavenging enzymes catalase, copper/zinc- and manganese-superoxide dismutase. As for COX-2, the three enzymes were up-regulated in the hippocampus at pnd 1 and returned at or below baseline by pnd 4. In the cortex, only PSEN 1 and 2 showed a moderate up-regulation at pnd 1 followed by a down-regulation at pnd 11. These findings suggest that moderate perinatal hypoxic episodes are associated with a dysregulation of the several genes involved in brain development and anti-oxidant defenses, which follows a rapid and transient oxidative stress. Such alterations are particularly evident in the hippocampus and could represent an adaptive response to the hypoxic condition. The delayed down-regulation of the scavenging enzymes could set the ground for brain damage and delayed behavioral alterations and further support the potential benefit of early anti-oxidant treatments in a short therapeutic window soon after birth.
环氧化酶-2（COX-2）以及早老素（PSEN）1和2基因在发育过程以及与缺氧相关的病理状况中受到调控。在本研究中，我们在中度围产期全脑窒息大鼠模型中，调查了出生后前两周它们的表达模式，我们之前报道该模型的特征为早期氧化应激和行为改变延迟。在海马体中，围产期全脑窒息诱导COX-2 mRNA早期上调（出生后第1天，pnd 1），这早于PSEN 1和2基因的上调，后者在pnd 4时观察到。在pnd 11时，与对照动物相比，所有三个基因的表达均降低。此外，我们分析了清除酶过氧化氢酶、铜/锌超氧化物歧化酶和锰超氧化物歧化酶的表达。与COX-2一样，这三种酶在pnd 1时在海马体中上调，并在pnd 4时恢复到基线或低于基线水平。在皮质中，只有PSEN 1和2在pnd 1时表现出中度上调，随后在pnd 11时下调。这些发现表明，中度围产期缺氧发作与参与脑发育和抗氧化防御的多个基因的失调有关，这是在快速且短暂的氧化应激之后发生的。这种改变在海马体中尤为明显，可能代表对缺氧状况的一种适应性反应。清除酶的延迟下调可能为脑损伤和行为改变延迟奠定基础，并进一步支持出生后不久在短治疗窗口内进行早期抗氧化治疗的潜在益处。
