Potter Molly, Rosenkrantz Ted, Fitch R Holly
University of Connecticut Health Center, School of Medicine, Farmington, CT, United States.
University of Connecticut Health Center, Dept. of Pediatrics/Neonatology, Farmington, CT, United States.
Int J Dev Neurosci. 2018 Nov;70:46-55. doi: 10.1016/j.ijdevneu.2018.02.001. Epub 2018 Feb 21.
The current study investigated behavioral and post mortem neuroanatomical outcomes in Wistar rats with a neonatal hypoxic-ischemic (HI) brain injury induced on postnatal day 6 (P6; Rice-Vannucci HI method; Rice et al., 1981). This preparation models brain injury seen in premature infants (gestational age (GA) 32-35 weeks) based on shared neurodevelopmental markers at time of insult, coupled with similar neuropathologic sequelae (Rice et al., 1981; Workman et al., 2013). Clinically, HI insult during this window is associated with poor outcomes that include attention deficit hyperactivity disorder (ADHD), motor coordination deficits, spatial memory deficits, and language/learning disabilities. To assess therapies that might offer translational potential for improved outcomes, we used a P6 HI rat model to measure the behavioral and neuroanatomical effects of two prospective preterm neuroprotective treatments - hypothermia and caffeine. Hypothermia (aka "cooling") is an approved and moderately efficacious intervention therapy for fullterm infants with perinatal hypoxic-ischemic (HI) injury, but is not currently approved for preterm use. Caffeine is a respiratory stimulant used during removal of infants from ventilation but has shown surprising long-term benefits, leading to consideration as a therapy for HI of prematurity. Current findings support caffeine as a preterm neuroprotectant; treatment significantly improved some behavioral outcomes in a P6 HI rat model and partially rescued neuropathology. Hypothermia treatment (involving core temperature reduction by 4 °C for 5 h), conversely, was found to be largely ineffective and even deleterious for some measures in both HI and sham rats. These results have important implications for therapeutic intervention in at-risk preterm populations, and promote caution in the application of hypothermia protocols to at-risk premature infants without further research.
本研究调查了出生后第6天（P6；采用赖斯-万努奇缺氧缺血性（HI）脑损伤方法；赖斯等人，1981年）诱导产生新生儿缺氧缺血性（HI）脑损伤的Wistar大鼠的行为和死后神经解剖学结果。该模型基于损伤时共同的神经发育标志物以及相似的神经病理后遗症，模拟了早产儿（胎龄（GA）32 - 35周）所见的脑损伤（赖斯等人，1981年；沃克曼等人，2013年）。临床上，在此窗口期的HI损伤与包括注意力缺陷多动障碍（ADHD）、运动协调缺陷、空间记忆缺陷以及语言/学习障碍在内的不良后果相关。为了评估可能具有改善预后转化潜力的治疗方法，我们使用P6 HI大鼠模型来测量两种前瞻性早产神经保护治疗——低温疗法和咖啡因的行为和神经解剖学效应。低温疗法（又称“降温”）是一种已获批准且对足月围产期缺氧缺血性（HI）损伤婴儿中度有效的干预疗法，但目前尚未批准用于早产婴儿。咖啡因是在婴儿撤离通气时使用的呼吸兴奋剂，但已显示出令人惊讶的长期益处，因此被考虑作为治疗早产HI的一种疗法。目前的研究结果支持咖啡因作为一种早产神经保护剂；在P6 HI大鼠模型中，该治疗显著改善了一些行为结果，并部分挽救了神经病理学变化。相反，低温治疗（将核心体温降低4°C持续5小时）在HI大鼠和假手术大鼠中对某些指标在很大程度上无效甚至有害。这些结果对高危早产人群的治疗干预具有重要意义，并促使在没有进一步研究的情况下，在将低温方案应用于高危早产儿时要谨慎。
