Robinson Shenandoah, Winer Jesse L, Chan Lindsay A S, Oppong Akosua Y, Yellowhair Tracylyn R, Maxwell Jessie R, Andrews Nicholas, Yang Yirong, Sillerud Laurel O, Meehan William P, Mannix Rebekah, Brigman Jonathan L, Jantzie Lauren L
Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
Front Neurol. 2018 Jun 19;9:451. doi: 10.3389/fneur.2018.00451. eCollection 2018.
Survivors of infant traumatic brain injury (TBI) are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high-dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose × 6d) to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12) controlled-cortical impact (CCI) model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI). Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI.
婴儿创伤性脑损伤（TBI）幸存者容易出现慢性神经功能缺损，给个人和社会带来终身负担。新型干预措施向临床试验的转化部分受到缺乏真正具有代表性的认知临床前测试以及功能结果相应生物标志物的阻碍。为了填补这一空白，在大鼠出生后第12天（P12）的控制性皮质撞击（CCI）模型中，使用触摸屏操作箱和扩散张量成像（DTI）区域分析，测试了高剂量、延长的损伤后促红细胞生成素（EPO，3000U/kg/剂量×6天）方案预防慢性认知和影像学缺损的能力。结果表明，EPO可预防婴儿TBI后的功能损伤和MRI损伤。具体而言，P30时的亚急性DTI显示出广泛的微观结构损伤，而EPO可预防这种损伤。在触摸屏操作箱平台上对视觉辨别能力的评估表明，所有组都能进行视觉辨别。然而，与假手术组和CCI-EPO组大鼠相比，接受赋形剂治疗的CCI大鼠未能通过逆向学习，且出现了持续性错误。P90时的慢性DTI显示，EPO治疗可预防对侧白质和同侧外侧前额叶皮质损伤。这种DTI改善与认知表现相关。综上所述，在婴儿TBI的转化临床前模型中，延长EPO治疗可恢复成年大鼠的执行功能，并预防有认知缺陷大鼠的脑微观结构异常。使用触摸屏操作箱和区域DTI分析进行的精密测试可能会加快从临床前研究到临床试验的干预措施的转化和有效产出。总体而言，这些数据支持在人类婴儿TBI的临床试验中使用EPO。
