A Ferret Model of Encephalopathy of Prematurity.
A Ferret Model of Encephalopathy of Prematurity.
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早产儿脑病的雪貂模型。
DOI：
10.1159/000498968
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发表时间：
2018
影响因子：
2.9
通讯作者：
Juul,SandraE
中科院分区：
文献类型：
--
作者：
Wood,Thomas;Moralejo,Daniel;Corry,Kylie;Snyder,JessicaM;Traudt,Christopher;Curtis,Chad;Nance,Elizabeth;Parikh,Pratik;Juul,SandraE
目前需要相关的动物模型来测试早产儿神经系统后遗症的治疗干预措施。雪貂是一个有吸引力的模型物种，因为它有一个脑回化的大脑，其白质与灰质的比例与人类大脑相似。在出生后第10天（P10）雪貂套件中开发了早产儿脑病模型，认为其发育相当于妊娠24-26周的婴儿。交叉培养的P10雪貂试剂盒在经历连续的缺氧-高氧-缺氧（9%下60分钟，60%下120分钟和9%下30分钟）之前接受5 mg/kg的脂多糖（LPS）。对照组动物接受生理盐水溶剂，然后接受常氧。在P28和P70之间评估了基本反射（负趋地性、悬崖厌恶和翻正）以及自动化猫道上的步态协调的发展，然后进行离体磁共振成像（MRI）和免疫组织化学分析。与对照组相比，受伤的动物在P28和P40之间具有较慢的整体反射发育，以及与P42时的“脚趾行走”一致的较小的后爪区域。由于步态协调性降低，受伤动物在猫步评估期间也表现出明显更大的侧向运动。离体MRI显示T2加权成像上广泛的白质高信号以及改变的连接模式。这与以髓鞘碱性蛋白染色强度增加、白质变薄和少突胶质细胞转录因子2（OLIG 2）阳性细胞丢失为特征的白质发育不良相一致。这些结果表明，病理和运动缺陷与过早的白质损伤一致。因此，这种新生雪貂模型可以提供一个额外的平台，在转化为人类临床试验之前评估潜在的治疗方法。
There is an ongoing need for relevant animal models in which to test therapeutic interventions for infants with neurological sequelae of prematurity. The ferret is an attractive model species as it has a gyrified brain with a white-to-gray matter ratio similar to that in the human brain. A model of encephalopathy of prematurity was developed in postnatal day 10 (P10) ferret kits, considered to be developmentally equivalent to infants of 24–26 weeks’ gestation. Cross-fostered P10 ferret kits received 5 mg/kg of lipopolysaccharide (LPS) before undergoing consecutive hypoxia-hyperoxia-hypoxia (60 min at 9%, 120 min at 60%, and 30 min at 9%). Control animals received saline vehicle followed by normoxia. The development of basic reflexes (negative geotaxis, cliff aversion, and righting) as well as gait coordination on an automated catwalk were assessed between P28 and P70, followed by ex vivo magnetic resonance imaging (MRI) and immunohistochemical analysis. Compared to controls, injured animals had slower overall reflex development between P28 and P40, as well as smaller hind-paw areas consistent with “toe walking” at P42. Injured animals also displayed significantly greater lateral movement during CatWalk assessment as a result of reduced gait coordination. Ex vivo MRI showed widespread white-matter hyperintensity on T2-weighted imaging as well as altered connectivity patterns. This coincided with white-matter dysmaturation characterized by increased intensity of myelin basic protein staining, white-matter thinning, and loss of oligodendrocyte transcription factor 2 (OLIG2)-positive cells. These results suggest both pathological and motor deficits consistent with premature white-matter injury. This newborn ferret model can therefore provide an additional platform to assess potential therapies before translation to human clinical trials.