缺氧-复氧缺血性新生脑损伤体内模型评估粒细胞集落刺激因子/干细胞因子和 Fms 相关酪氨酸激酶 3 配体的短期、中期和长期作用。
Short-, Mid-, and Long-Term Effect of Granulocyte Colony-Stimulating Factor/Stem Cell Factor and Fms-Related Tyrosine Kinase 3 Ligand Evaluated in an In Vivo Model of Hypoxic-Hyperoxic Ischemic Neonatal Brain Injury.
机构信息
Department of Pediatrics II (Neonatology), Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
Kinderklinik Dritter Orden, Munich Technical University, Bischof Altmann-Strasse 9, 94032 Passau, Germany.
出版信息
Biomed Res Int. 2019 Mar 13;2019:5935279. doi: 10.1155/2019/5935279. eCollection 2019.
Hematopoietic growth factors are considered to bear neuroprotective potential. We have previously shown that delayed treatment with granulocyte colony-stimulating factor (G-CSF)/stem cell factor (SCF) and Fms-related tyrosine kinase 3 ligand (FL) ameliorates excitotoxic neonatal brain injury. The effect of these substances in combined-stressor neonatal brain injury models more closely mimicking clinical conditions has not been investigated. The aim of this study was to assess the short-, mid-, and long-term neuroprotective potential of G-CSF/SCF and FL in a neonatal model of hypoxic-hyperoxic ischemic brain injury. Five-day-old (P5) CD-1 mice were subjected to unilateral common carotid artery ligation and subsequent alternating periods of hypoxia and hyperoxia for 65 minutes. Sixty hours after injury, pups were randomly assigned to intraperitoneal treatment with (i) G-CSF (200 g/kg)/SCF (50 g/kg), (ii) FL (100 g/kg), or (iii) vehicle every 24 hours for three or five consecutive days. Histopathological and functional outcomes were evaluated on P10, P18, and P90. Baseline outcome parameters were established in sham-treated and healthy control animals. Gross brain injury did not significantly differ between treatment groups at any time point. On P10, caspase-3 activation and caspase-independent apoptosis were similar between treatment groups; cell proliferation and the number of BrdU-positive vessels did not differ on P18 or P90. Neurobehavioral assessment did not reveal significant differences between treatment groups in accelerod performance, open field behavior, or novel object recognition capacity on P90. Turning behavior was more frequently observed in G-CSF/SCF- and FL-treated animals. No sex-specific differences were detected in any outcome parameter evaluated. In hypoxic-hyperoxic ischemic neonatal brain injury, G-CSF/SCF and FL treatment does not convey neuroprotection. Prior to potential clinical use, meticulous assessment of these hematopoietic growth factors is mandated.
造血生长因子被认为具有神经保护潜力。我们之前已经表明，延迟使用粒细胞集落刺激因子（G-CSF）/干细胞因子（SCF）和 Fms 相关酪氨酸激酶 3 配体（FL）可改善新生鼠兴奋性毒性脑损伤。这些物质在更接近临床情况的联合应激新生鼠脑损伤模型中的作用尚未得到研究。本研究的目的是评估 G-CSF/SCF 和 FL 在新生鼠缺氧-复氧缺血性脑损伤模型中的短期、中期和长期神经保护潜力。5 日龄（P5）CD-1 小鼠接受单侧颈总动脉结扎，随后进行 65 分钟的缺氧和复氧交替期。损伤后 60 小时，幼鼠随机接受腹腔内注射（i）G-CSF（200μg/kg）/SCF（50μg/kg）、（ii）FL（100μg/kg）或（iii）载体，每 24 小时一次，连续 3 或 5 天。在 P10、P18 和 P90 评估组织病理学和功能结果。在假处理和健康对照动物中建立了基线结果参数。在任何时间点，治疗组之间的大体脑损伤均无显著差异。在 P10 时，各组之间的半胱天冬酶-3 激活和半胱天冬酶非依赖性凋亡相似；在 P18 或 P90 时，细胞增殖和 BrdU 阳性血管数量没有差异。在 P90 时，加速性能、旷场行为或新物体识别能力的神经行为评估未显示治疗组之间有显著差异。在 G-CSF/SCF 和 FL 处理的动物中，更频繁地观察到转向行为。在评估的任何结果参数中，均未检测到性别特异性差异。在新生鼠缺氧-复氧缺血性脑损伤中，G-CSF/SCF 和 FL 治疗并不能提供神经保护。在潜在的临床应用之前，需要对这些造血生长因子进行细致的评估。
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