Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats.
Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats.
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DOI：
10.3390/ijms242115583
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发表时间：
2023-10-25
影响因子：
5.6
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中科院分区：
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新生儿缺氧缺血性脑病（HIE）是足月新生儿死亡和慢性残疾的主要原因。低温（HT）是临床上唯一可用的治疗干预，然而，其神经保护作用是有限的。乳铁蛋白（LF）是牛奶中主要的乳清蛋白，具有铁结合、抗炎和抗凋亡的特性，并已显示出保护非常不成熟的大脑免受HI损伤。我们推测，结合早期口服LF全身低温可以增强神经保护在HIE大鼠模型。从（P6）开始，向妊娠Wistar大鼠喂食LF补充饲料（1 mg/kg）或对照饲料。在P7，雄性和雌性幼仔的右颈总动脉闭塞，随后缺氧（8% O2，60′）（HI）。缺氧后立即使用Criticool®进行低温（目标温度为32.5-33.5 °C）（持续5小时）。根据饮食、损伤和热条件对动物进行分组。在P8（HI后24 h），使用磁共振波谱（1H-MRS）评估脑神经化学特征，并使用高信号T2 W信号测量脑病变。在右侧海马中评估与神经元兴奋毒性、能量代谢和炎症相关的基因的mRNA水平。采用免疫荧光法检测右侧海马细胞标志物和凋亡表达。HI减少能量代谢产物并增加乳酸。在HI组中观察到的神经元-星形胶质细胞偶联损伤主要被HT逆转。LF对星形胶质细胞功能有重要影响，降低了与神经元兴奋性毒性相关的基因水平，恢复了与代谢支持相关的基因的mRNA水平。当结合时，LF和HT呈现出协同效应，并防止乳酸积累，减少炎症和减少脑损伤，指出结合这些疗法的益处。总之，我们发现乳铁蛋白通过不同的机制可以增强HT诱导的新生儿脑缺氧缺血后的神经保护作用。
Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O2 for 60′) (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5–33.5 °C) was performed (5 h duration) using Criticool®. The animals were divided according to diet, injury and thermal condition. At P8 (24 h after HI), the brain neurochemical profile was assessed using magnetic resonance spectroscopy (1H-MRS) and a hyperintense T2W signal was used to measure the brain lesions. The mRNA levels of the genes related to glutamatergic excitotoxicity, energy metabolism and inflammation were assessed in the right hippocampus. The cell markers and apoptosis expression were assessed using immunofluorescence in the right hippocampus. HI decreased the energy metabolites and increased lactate. The neuronal–astrocytic coupling impairments observed in the HI groups were reversed mainly by HT. LF had an important effect on astrocyte function, decreasing the levels of the genes related to glutamatergic excitotoxicity and restoring the mRNA levels of the genes related to metabolic support. When combined, LF and HT presented a synergistic effect and prevented lactate accumulation, decreased inflammation and reduced brain damage, pointing out the benefits of combining these therapies. Overall, we showed that through distinct mechanisms lactoferrin can enhance neuroprotection induced by HT following neonatal brain hypoxia-ischemia.
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