Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures
Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures
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DOI：
10.1159/000491859
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发表时间：
2018-01-01
期刊：
影响因子：
2.5
通讯作者：
Balduini, Walter
中科院分区：
文献类型：
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作者：
Carloni, Silvia;Facchinetti, Fabrizio;Balduini, Walter
背景：缺氧缺血性脑病是新生儿发病的主要原因。低温治疗虽然有益，但仍然使许多接受治疗的婴儿终身残疾。因此，需要辅助疗法（例如褪黑激素）来提供额外的神经保护。目的：本研究的目的是确定可与低温产生神经保护协同作用的褪黑激素浓度范围。方法：在新生大鼠的器官型海马切片培养物中通过短暂氧糖剥夺（OGD）模拟缺氧缺血。通过碘化丙啶 (PI) 标记来量化细胞损伤。结果：褪黑素以浓度依赖性方式（1-100μM）减少OGD诱导的细胞死亡，EC50约为25μM。低温以时间依赖性方式减弱细胞死亡，24小时暴露时几乎完全保护（78％），6小时暴露时部分保护（40％）。当褪黑激素的次最大有效浓度（25或50μM，产生54％和64％的保护）与6小时的低温相结合时，观察到几乎完全的保护（分别为73％和78％；p <0.05和p <0.01）。结论：褪黑激素与低温协同作用，可减轻 OGD 引起的器官型海马培养物损伤。这种还原论方法可以确定能够增强低温神经保护的褪黑激素的浓度范围。这些信息与药代动力学数据相结合，将有助于确定褪黑激素在体内以及最终在患者体内的治疗剂量。 (C) 2018 S. Karger AG，巴塞尔
Background: Hypoxic-ischemic encephalopathy is a major cause of neonatal morbidity. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Thus, adjunctive therapies, such as melatonin, are needed to provide additional neuroprotection. Objectives: The aim of this study was to determine a range of melatonin concentrations that could result in neuroprotective synergy with hypothermia. Methods: Hypoxia-ischemia was simulated by transient oxygen-glucose deprivation (OGD) in organotypic hippocampal slice cultures derived from neonatal rats. Cell damage was quantified by propidium iodide (PI) labeling. Results: Melatonin reduced OGD-induced cell death in a concentration-dependent manner (1-100 mu M) with an EC50 of about 25 mu M. Hypothermia attenuated cell death in a time-dependent manner, with a nearly full protection upon 24-h exposure (78%) and partial protection (40%) upon 6-h exposure. When submaximal effective concentrations of melatonin (25 or 50 mu M, resulting in 54 and 64% protection) were combined with 6 h of hypothermia, nearly full protection (73 and 78%, respectively; p < 0.05 and p < 0.01) was observed. Conclusion: Melatonin acts in synergy with hypothermia in attenuating OGD-induced damage in organotypic hippocampal cultures. This reductionist approach allows the determination of a range of concentrations of melatonin capable of enhancing hypothermic neuroprotection. This information, coupled with pharmacokinetic data, will help to define the therapeutic dosage of melatonin in vivo and, ultimately, in patients. (C) 2018 S. Karger AG, Basel