Sección Genética Evolutiva, Facultad de Ciencias, Universidad de la República (Udelar), Montevideo, Uruguay.
Dept. Neonatología, Facultad de Medicina, Universidad de la República (Udelar), Montevideo, Uruguay.
Neurochem Int. 2021 Jul;147:105064. doi: 10.1016/j.neuint.2021.105064. Epub 2021 May 2.
Hypoxic-ischemic encephalopathy (HIE) causes mortality and long-term neurologic morbidities in newborns, affecting pathways related to energy failure, excitotoxicity and oxidative stress that often lead to cell death. The whole process of HIE injury is coupled to changes in the expression of a great array of proteins. A nanoliposomal preparation of the flavonoid quercetin has been shown to exert neuroprotective effects in perinatal asphyxia models. This study aimed to identify neonatal HIE markers and explore the effect of quercetin administration in two perinatal asphyxia models: newborn rats and piglets. In the rat model, nanoliposomal quercetin administration reduced mortality after asphyxia. In the piglet model, quercetin partially overrode the reduction of HIF-1α mRNA levels in the cortex induced by asphyxia. Quercetin administration also reduced increased level of HO-1 mRNA in asphyctic piglets. These results suggest that quercetin neuroprotection might be involved in the regulation of HIF-1α, HO-1 and their targets. A proteomic approach revealed that the glycolytic pathway is strongly regulated by quercetin in both species. We also identified a set of proteins differentially expressed that could be further considered as markers. In piglets, this set includes Acidic Leucine-rich nuclear phosphoprotein 32 (ANP32A), associated with nervous system differentiation, proteins related with death pathways and alpha-enolase which can be converted to neuron-specific enolase, a glycolytic enzyme that may promote neuroprotection. In newborn rats, other promising proteins associated with neurogenesis and neuroprotection emerged, such as dihydropyrimidinase-related proteins, catalytic and regulatory subunits of phosphatases and heterogeneous nuclear ribonucleoprotein K (hnRNPK). Our results show that a nanoliposomal preparation of quercetin, with protective effect in two HIE mammal models, modulates the expression of proteins involved in energy metabolism and other putative neuroprotective signals in the cortex. Identification of these signals could reveal potential molecular pathways involved in disease onset and the novel quercetin neuroprotective strategy.
缺氧缺血性脑病（HIE）可导致新生儿死亡和长期神经系统病变，影响与能量衰竭、兴奋性毒性和氧化应激相关的途径，这些途径通常会导致细胞死亡。HIE 损伤的整个过程与大量蛋白质表达的变化有关。黄酮类槲皮素的纳米脂质体制剂已被证明在围产期窒息模型中具有神经保护作用。本研究旨在鉴定新生儿 HIE 标志物，并探讨在两种围产期窒息模型中给予槲皮素的效果：新生大鼠和仔猪。在大鼠模型中，纳米脂质体槲皮素给药可降低窒息后的死亡率。在仔猪模型中，槲皮素部分克服了窒息引起的皮质 HIF-1αmRNA 水平的降低。槲皮素给药还降低了窒息仔猪中 HO-1mRNA 的升高水平。这些结果表明，槲皮素的神经保护作用可能涉及 HIF-1α、HO-1 及其靶标的调节。蛋白质组学方法表明，在这两种物种中，糖酵解途径都受到槲皮素的强烈调节。我们还鉴定了一组差异表达的蛋白质，它们可以进一步被认为是标志物。在仔猪中，这一组包括酸性亮氨酸丰富核磷蛋白 32（ANP32A），与神经系统分化有关，与死亡途径有关的蛋白质和α-烯醇酶，它可以转化为神经元特异性烯醇酶，一种可能促进神经保护的糖酵解酶。在新生大鼠中，出现了其他与神经发生和神经保护相关的有前途的蛋白质，如二氢嘧啶酶相关蛋白、磷酸酶的催化和调节亚基以及异质核核糖核蛋白 K（hnRNPK）。我们的结果表明，具有两种 HIE 哺乳动物模型保护作用的槲皮素纳米脂质体制剂，可调节皮质中参与能量代谢和其他潜在神经保护信号的蛋白质的表达。鉴定这些信号可以揭示疾病发病的潜在分子途径和新的槲皮素神经保护策略。
