J Neurosurg. 2018 Nov 1;129(5):1286-1294. doi: 10.3171/2017.7.JNS17878. Epub 2018 Jan 26.
OBJECTIVETraumatic brain injury (TBI) is a major cause of long-term disability and death in young adults. The lack of pharmaceutical therapy for post-acute TBI recovery remains a crucial medical challenge. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), which are 2 key hematopoietic growth factors, have shown neuroprotective and neurorestorative effects in experimental stroke. The objective of this study was to determine the therapeutic efficacy of combined treatment (SCF + G-CSF) in subacute TBI.METHODSYoung-adult male C57BL mice were subject to TBI in the cortex of the right hemisphere. After TBI induction, mice were randomly divided into 2 groups: a vehicle control group and an SCF + G-CSF treatment group. Mice without TBI served as sham operative controls. Treatment was initiated 2 weeks after TBI induction. SCF (200 μg/kg) and G-CSF (50 μg/kg) or an equal volume of vehicle solution was subcutaneously injected daily for 7 days. A battery of neurobehavioral tests for evaluation of memory and cognitive function (water maze and novel object recognition tests), anxiety (elevated plus maze test), and motor function (Rota-Rod test) was performed during the period of 2-9 weeks after treatment. Neurodegeneration and dendritic density in both hemispheres were determined through histochemistry and immunohistochemistry at 11 weeks posttreatment.RESULTSWater maze testing showed that TBI-impaired spatial learning and memory was restored by SCF + G-CSF treatment. The findings from the elevated plus maze tests revealed that SCF + G-CSF treatment recovered TBI-caused anxiety and risk-taking behavior. There were no significant differences between the treated and nontreated TBI mice in both the Rota-Rod test and novel object recognition test. In the brain sections, the authors observed that widespread degenerating neurons were significantly increased in both hemispheres in the TBI-vehicle control mice. TBI-induced increases in neurodegeneration were significantly reduced by SCF + G-CSF treatment in the contralateral hemisphere, making it no different from that of the sham controls. Dendritic density in the frontal cortex of the contralateral hemisphere was significantly reduced in the TBI-vehicle control mice, whereas SCF + G-CSF-treated TBI mice showed significant increases of the dendritic density in the same brain region. SCF + G-CSF-treated TBI mice also showed a trend toward increasing dendritic density in the contralateral hippocampus.CONCLUSIONSSCF + G-CSF treatment in the subacute phase of TBI restored TBI-impaired spatial learning and memory, prevented posttraumatic anxiety and risk-taking behavior, inhibited TBI-induced neurodegeneration, and enhanced neural network remodeling. These findings suggest the therapeutic potential of hematopoietic growth factors for brain repair in the subacute phase of TBI.
创伤性脑损伤（TBI）是年轻成年人长期残疾和死亡的主要原因。缺乏用于急性后期 TBI 康复的药物治疗仍然是一个关键的医学挑战。干细胞因子（SCF）和粒细胞集落刺激因子（G-CSF）是两种关键的造血生长因子，在实验性中风中显示出神经保护和神经修复作用。本研究的目的是确定联合治疗（SCF+G-CSF）在亚急性 TBI 中的治疗效果。
年轻成年雄性 C57BL 小鼠在右侧大脑皮层接受 TBI。TBI 诱导后，小鼠随机分为 2 组：载体对照组和 SCF+G-CSF 治疗组。未接受 TBI 的小鼠作为假手术对照。治疗在 TBI 诱导后 2 周开始。SCF（200μg/kg）和 G-CSF（50μg/kg）或等量载体溶液每天皮下注射，持续 7 天。在治疗后 2-9 周期间，通过水迷宫和新物体识别测试进行一系列用于评估记忆和认知功能的神经行为测试（水迷宫和新物体识别测试）、焦虑（高架十字迷宫测试）和运动功能（转棒测试）。在治疗后 11 周，通过组织化学和免疫组织化学确定双侧半球的神经退行性变和树突密度。
水迷宫测试表明，SCF+G-CSF 治疗恢复了 TBI 引起的空间学习和记忆障碍。高架十字迷宫测试的结果表明，SCF+G-CSF 治疗恢复了 TBI 引起的焦虑和冒险行为。在转棒测试和新物体识别测试中，治疗组和未治疗组的 TBI 小鼠之间均无显著差异。在大脑切片中，作者观察到 TBI-载体对照组的双侧半球广泛的变性神经元明显增加。SCF+G-CSF 治疗显著降低了 TBI 诱导的神经退行性变，使其与假手术对照组无差异。TBI-载体对照组的对侧皮质的树突密度显著降低，而 SCF+G-CSF 治疗的 TBI 小鼠在同一脑区的树突密度显著增加。SCF+G-CSF 治疗的 TBI 小鼠在对侧海马区的树突密度也有增加的趋势。
在 TBI 的亚急性期，SCF+G-CSF 治疗恢复了 TBI 引起的空间学习和记忆障碍，预防了创伤后焦虑和冒险行为，抑制了 TBI 诱导的神经退行性变，并增强了神经网络重塑。这些发现表明，造血生长因子在 TBI 的亚急性期具有治疗脑损伤的潜力。
