Citalopram enhances neurovascular regeneration and sensorimotor functional recovery after ischemic stroke in mice.
Citalopram enhances neurovascular regeneration and sensorimotor functional recovery after ischemic stroke in mice.
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DOI：
10.1016/j.neuroscience.2013.04.011
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发表时间：
2013-09-05
期刊：
影响因子：
3.3
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Espinera AR;Ogle ME;Gu X;Wei L
最近的临床试验表明，选择性5-羟色胺再摄取抑制剂（SSRIs）治疗后，中风促进运动功能的恢复，但其潜在的机制仍有待进一步阐明。我们假设每天服用临床药物西酞普兰会通过增强缺血性梗死周围区域的神经血管修复而产生这些功能益处。为了验证这一假设，通过永久性结扎大脑中动脉远端分支至桶状皮质并闭塞双侧颈总动脉7分钟，在雄性C57/B6小鼠中诱导局灶性缺血性中风。西酞普兰（10 mg/kg，i. p.）在中风后24小时注射，此后每天注射。为了标记增殖细胞，在中风后3天开始每天注射溴脱氧尿苷。进行免疫组织化学和功能测定以阐明中风后西酞普兰介导的细胞和感觉运动变化。西酞普兰治疗对卒中后3天的梗死形成或水肿没有显著影响;然而，在粘附物去除试验中，西酞普兰治疗的小鼠在卒中后3天和14天的功能恢复优于盐水治疗的对照组。在西酞普兰治疗的动物中风后7天，在梗死周围区域检测到脑源性神经营养因子表达增加。在中风后7天，西酞普兰治疗的小鼠中增殖的神经祖细胞的数量和成神经细胞从脑室下区向缺血皮质迁移的距离显著更大。免疫组织化学染色和共定位分析表明，西酞普兰治疗的动物产生更多的新的神经元和微血管在梗死周围区域中风后21和28天。总之，这些结果表明，西酞普兰促进中风后感觉运动的恢复可能通过增强神经发生，神经细胞迁移和微血管的支持在缺血性脑梗死周围区域。
Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of the ischemic brain.