Citalopram enhances neurovascular regeneration and sensorimotor functional recovery after ischemic stroke in mice

Abstract

Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors 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 (10mg/kg, i.p.) was injected 24h 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 toward 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.

Keywords: 2,3,5-triphenyltetrazolium chloride; ANOVA; BDNF; BrdU; DCX; MCA; MCAO; NIHSS; National Institutes of Health stroke scale; NeuN; OCT; PBS; SD; SSRI; SVZ; TTC; TrkB; analysis of variance; angiogenesis; brain-derived neurotrophic factor; bromodeoxyuridine; citalopram; doublecortin; ischemic stroke; middle cerebral artery; middle cerebral artery occlusion; neurogenesis; neuronal nuclei; optimal cutting temperature; phosphate-buffered saline; selective serotonin reuptake inhibitor; standard deviation; sub-ventricular zone; tyrosine kinase receptor.