Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity
Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity
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DOI：
10.1177/0271678x16648971
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发表时间：
2017-03
影响因子：
6.3
通讯作者：
Ya-Chao Wang;E. Sanchez-Mendoza;T. Doeppner;D. Hermann
中科院分区：
文献类型：
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作者：
Ya-Chao Wang;E. Sanchez-Mendoza;T. Doeppner;D. Hermann
NMDA拮抗剂美金刚优先抑制突触外NMDA受体，后者在中风时过度激活，被认为干扰神经可塑性。我们假设美金刚可增强脑缺血后的神经恢复、脑重塑和可塑性。建立C57BL6/j小鼠大脑中动脉闭塞模型。从中风后72小时开始，赋形剂或美金胺(4或20毫克/公斤/天)皮下注射持续28天。在49天内评估神经功能恢复、皮损周围组织重塑和对侧锥体束可塑性。每天服用20毫克/公斤而不是4毫克/公斤的美金刚，持续改善运动协调和空间记忆。美金刚可减轻继发性纹状体萎缩。这种延迟的神经保护与减少星形胶质细胞和增加梗塞边缘周围的毛细血管形成有关。美金刚可使双侧纹状体和皮质中BDNF、GDNF和VEGF的浓度升高。顺行追踪研究表明，美金刚增加了对侧皮质黑质在中线方向的发芽，指向单侧红核。在对侧运动皮质，美金胺作用14天后，主要表达于突触外NMDA受体的NMDA受体亚单位GluN2B一过性减少，而优先与突触NMDA受体共定位的GluN2A和PSD-95在28天后增加。我们的数据提示美金刚对促进急性卒中后恢复的效用。
The NMDA antagonist memantine preferentially inhibits extrasynaptic NMDA receptors, which are overactivated upon stroke and thought to disturb neuroplasticity. We hypothesized that memantine enhances post-ischemic neurological recovery, brain remodeling, and plasticity. C57BL6/j mice were exposed to intraluminal middle cerebral artery occlusion. Starting 72 hours post-stroke, vehicle or memantine (4 or 20 mg/kg/day) were subcutaneously delivered over 28 days. Neurological recovery, perilesional tissue remodeling and contralesional pyramidal tract plasticity were evaluated over 49 days. Memantine, delivered at 20 but not 4 mg/kg/day, persistently improved motor-coordination and spatial memory. Secondary striatal atrophy was reduced by memantine. This delayed neuroprotection was associated with reduced astrogliosis and increased capillary formation around the infarct rim. Concentrations of BDNF, GDNF, and VEGF were bilaterally elevated by memantine in striatum and cortex. Anterograde tract tracing studies revealed that memantine increased contralesional corticorubral sprouting across the midline in direction to the ipsilesional red nucleus. In the contralesional motor cortex, the NMDA receptor subunit GluN2B, which is predominantly expressed in extrasynaptic NMDA receptors, was transiently reduced by memantine after 14 days, whereas GluN2A and PSD-95, which preferentially co-localize with synaptic NMDA receptors, were increased after 28 days. Our data suggest the utility of memantine for enhancing post-acute stroke recovery.