Zaghloul Nahla, Patel Hardik, Ahmed Mohamed Nagy
Department of Pediatrics, Division of Neonatology, Cohen Children's Medical Center of New York, New Hyde Park, New York, United States of America.
Feinstein institute for Medical Research, Manhasset, New York, United States of America.
PLoS One. 2017 Apr 13;12(4):e0175438. doi: 10.1371/journal.pone.0175438. eCollection 2017.
Periventricular leukomalacia (PVL), a brain injury affecting premature infants is commonly associated with cerebral palsy. PVL results from hypoxia-ischemia (HI) with or without infection and is characterized by white matter necrotic lesions, hypomyelination, microglial activation, astrogliosis, and neuronal death. It is important to study a PVL mouse model that mimics human PVL in symptomatology, anatomic and molecular basis. In our neonate mice model, bilateral carotid arteries were temporary ligated at P5 followed by hypoxic exposure (FiO2 of 8% for 20 min.). At P5 in mice, the white matter is more vulnerable to HI injury than the grey matter. In our PVL model, mice suffer from significant hind limb paresis, incoordination and feeding difficulties. Histologically they present with ventriculomegally, white matter loss, microglial activation and neuronal apoptosis. HI injury increases proinflammtory cytokines, activates NF-kB, activates microglia and causes nitrative stress. All these inflammatory mediators lead to oligodendroglial injury and white matter loss. Neurobehavioral analysis in the PVL mice model at P60 showed that the HI group had a significant decrease in hind limb strength, worsening rotarod testing and worsening performance in the open field test. This new PVL model has great advantages far beyond just mimicking human PVL in clinical features and histopathology. Long term survival, the development of cerebral palsy and the ability of using this model in transgenic animals will increase our understanding of the mechanistic pathways underlying PVL and defining specific targets for the development of suitable therapeutics.
脑室周围白质软化症（PVL）是一种影响早产儿的脑损伤，通常与脑瘫相关。PVL由缺氧缺血（HI）伴或不伴感染引起，其特征为白质坏死性病变、髓鞘形成不足、小胶质细胞活化、星形胶质细胞增生和神经元死亡。研究一种在症状学、解剖学和分子基础上模拟人类PVL的PVL小鼠模型很重要。在我们的新生小鼠模型中，在出生后第5天（P5）暂时结扎双侧颈动脉，随后进行低氧暴露（吸入氧分数为8%，持续20分钟）。在小鼠出生后第5天，白质比灰质更容易受到HI损伤。在我们的PVL模型中，小鼠出现明显的后肢麻痹、共济失调和进食困难。组织学上，它们表现为脑室扩大、白质丢失、小胶质细胞活化和神经元凋亡。HI损伤会增加促炎细胞因子，激活核因子-κB（NF-κB），激活小胶质细胞并导致硝化应激。所有这些炎症介质都会导致少突胶质细胞损伤和白质丢失。对PVL小鼠模型在出生后第60天（P60）进行的神经行为分析表明，HI组后肢力量显著下降，转棒试验表现恶化，旷场试验表现也恶化。这个新的PVL模型具有很大的优势，远远不止于在临床特征和组织病理学上模拟人类PVL。长期存活、脑瘫的发展以及在转基因动物中使用该模型的能力将增进我们对PVL潜在机制途径的理解，并确定开发合适治疗方法的特定靶点。
