Schober Michelle E, Requena Daniela F, Block Benjamin, Davis Lizeth J, Rodesch Christopher, Casper T Charles, Juul Sandra E, Kesner Raymond P, Lane Robert H
1 Department of Pediatrics, Division of Critical Care, University of Utah , Salt Lake City, Utah.
J Neurotrauma. 2014 Feb 15;31(4):358-69. doi: 10.1089/neu.2013.2922.
Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model.
We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI).
EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2.
EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury.
创伤性脑损伤（TBI）是儿童后天性神经残疾的主要原因。促红细胞生成素（EPO）是一种抗凋亡细胞因子，可改善成年大鼠脑外伤后的认知结果。据我们所知，尚未在发育性TBI模型中对EPO进行研究。
我们假设EPO可改善17日龄（P17）大鼠幼崽在控制性皮质撞击（CCI）后的认知结果，并增加海马中的神经元比例。
在CCI后1、24和48小时以及伤后第7天给予EPO或赋形剂。在伤后第14天使用新物体识别（NOR）评估认知结果。在伤后的前14天测量海马EPO水平、半胱天冬酶活性以及凋亡因子Bcl2、Bax、Bcl-xL和Bad的mRNA水平。在伤后第2天研究CA1、CA3和齿状回（DG）中的神经元比例和半胱天冬酶激活情况。
EPO使CCI后的识别记忆恢复正常。EPO减弱了CCI在伤后第1天而非第2天诱导的海马半胱天冬酶活性增加。EPO在伤后第2天增加了CA3中的神经元比例。相对于内源性EPO，外源性EPO的脑内水平似乎较低。EPO给药时间与海马EPO和促凋亡因子mRNA水平的时间变化相关。结论/推测：EPO改善了CCI后P17大鼠的识别记忆，增加了海马局部的神经元比例，并降低了半胱天冬酶活性。我们推测，EPO改善了大鼠幼崽CCI后的认知结果，这是由于在损伤后早期通过抑制半胱天冬酶依赖性凋亡改善了神经元存活。
