Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage
Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage
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DOI：
10.1016/j.neuropharm.2018.11.020
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发表时间：
2019-03-01
影响因子：
4.7
通讯作者：
Martinez-Orgado, Jose
中科院分区：
文献类型：
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作者：
Barata, Lorena;Arruza, Luis;Martinez-Orgado, Jose
目的：低温是缺氧缺血性损伤后的金标准，但对所有接受治疗的新生儿并不有益。大麻二酚在新生儿缺氧缺血性脑病动物模型中具有神经保护作用。本研究比较了大麻二酚和低温在新生缺氧缺血性仔猪中的相对功效，并评估了添加大麻二酚是否增强低温神经保护作用。方法：将一日龄HI（颈动脉钳夹和FiO（2）10%持续20分钟）仔猪随机分配至载体或大麻二酚1 mg/kg i.v.u.i.d.。在接受正常体温或48小时长的低温，随后复温6小时后，未操作的仔猪（未处理）作为对照。在整个实验过程中监测血液动力学或呼吸参数以及脑活动（aEEG振幅）。处死后，取脑进行组织学检查。（TUNEL染色，细胞凋亡; Iba-1免疫组织化学，小胶质细胞），生化（蛋白质羰基化，氧化应激;和TNF α浓度，神经炎症）或质子磁共振波谱（Lac/NAA：代谢紊乱; Glu/NAA：细胞毒性）。结果：HI导致持续抑郁的大脑活动和增加的小胶质细胞活化，这是显着改善大麻二酚单独或与低温，但不是单独的低温。缺氧缺血诱导的Lac/NAA、Glu/NAA、TNFa或细胞凋亡的增加不被单独的低温或大麻二酚逆转，但联合治疗可以逆转。没有处理修改HI对氧化应激或星形胶质细胞活化的影响。Cannabidiol treatment was well tolered.Conclusions：cannabidiol administration后缺氧缺血小猪提供了一些神经保护作用，但大麻二酚和低温的组合显示出一些附加效应，导致更完整的神经保护比单独的cannabidiol或低温。
Objective: Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated new-borns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection.Methods: One day-old HI (carotid clamp and FiO(2) 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (nave) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNF alpha concentration, neuroin-flammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: ex-citotoxicity).Results: HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFa or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated.Conclusions: cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone.