San Francisco Veteran's Affairs Medical Center, San Francisco, California, USA.
J Neurotrauma. 2011 Feb;28(2):259-68. doi: 10.1089/neu.2010.1648.
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.
选择性 5-羟色胺再摄取抑制剂氟西汀可诱导海马神经发生，刺激成年海马神经元的成熟和突触可塑性，并减轻多种中枢神经系统疾病中的运动/感觉和记忆障碍。在创伤性脑损伤 (TBI) 中，其对神经可塑性和功能的影响尚未得到彻底研究。在这里，我们研究了氟西汀在中重度 TBI 后的疗效，该 TBI 是通过皮质撞击控制产生的。TBI 或假手术后 3 天，用氟西汀（10mg/kg/d）或载体对小鼠进行 4 周治疗。为了评估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。齿状回的立体学分析显示，与对照组相比，用氟西汀治疗的脑损伤动物中双皮质素阳性细胞显著增加，这一发现与增强的海马神经发生一致。免疫组织化学和定量 Western 免疫印迹分别显示，脑损伤动物用氟西汀治疗后，表观遗传修饰（包括组蛋白 3 乙酰化增加和参与 DNA 甲基化的转录因子甲基-CpG 结合蛋白的诱导）也同样存在。为了确定氟西汀是否改善 TBI 后的神经功能结局，通过 CatWalk 辅助步态测试和 Barnes 迷宫测试分别评估步态功能和空间学习和记忆。在氟西汀和载体处理的动物之间未观察到这些参数的差异。因此，虽然氟西汀增强了 TBI 后海马的神经可塑性，但慢性给药并不能恢复运动功能或改善记忆缺陷。
