Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury.
Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury.
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DOI：
10.1089/neu.2010.1648
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发表时间：
2011-02
影响因子：
4.2
通讯作者：
Yonggang Wang;Melanie Neumann;Katharina Hansen;Shuwhey M Hong;Sharon Kim;L. Noble-Haeusslein;Jialing Liu
中科院分区：
文献类型：
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作者：
Yonggang Wang;Melanie Neumann;Katharina Hansen;Shuwhey M Hong;Sharon Kim;L. Noble-Haeusslein;Jialing Liu
选择性5-羟色胺再摄取抑制剂氟西汀诱导海马神经发生，刺激成年海马神经元的成熟和突触可塑性，并减少几种CNS疾病中的运动/感觉和记忆障碍。在创伤性脑损伤（TBI）的背景下，其对神经可塑性和功能的影响尚未得到彻底的研究。在这里，我们研究了氟西汀的疗效后，中度至重度TBI，所产生的控制皮质的影响。TBI或假手术后三天，用氟西汀（10 mg/kg/d）或载体治疗小鼠4周。为了评价氟西汀对神经可塑性的影响，研究了海马神经发生和表观遗传修饰。齿状回的体视学分析显示，与对照组相比，氟西汀治疗的脑损伤动物中doublecortin阳性细胞显著增加，这一发现与海马神经发生增强一致。表观遗传修饰，包括组蛋白3乙酰化的增加和甲基-CpG结合蛋白（一种参与DNA甲基化的转录因子）的诱导，同样分别通过免疫组织化学和定量Western免疫印迹在氟西汀治疗的脑损伤动物中观察到。为了确定氟西汀是否改善TBI后的神经功能结局，分别通过CatWalk辅助步态试验和巴恩斯迷宫试验评估步态功能和空间学习和记忆。氟西汀和溶剂处理动物之间未观察到这些参数的差异。因此，尽管氟西汀增强了TBI后海马的神经可塑性，但其长期给药并不能恢复运动功能或改善记忆缺陷。
The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits.