Neurology, David Geffen School of Medicine at UCLA.
Anatomy and Psychology, University of Otago.
Stroke. 2014 Jul;45(7):2093-2100. doi: 10.1161/STROKEAHA.113.004476. Epub 2014 Jun 17.
Stroke treatment is constrained by limited treatment windows and the clinical inefficacy of agents that showed preclinical promise. Yet animal and clinical data suggest considerable poststroke plasticity, which could allow treatment with recovery-modulating agents. Memantine is a well-tolerated N-methyl-D-aspartate glutamate receptor antagonist in common use for Alzheimer disease.
Memantine, 30 mg/kg per day, or vehicle, was delivered chronically in drinking water beginning >2 hours after photothrombotic stroke.
Although there was no difference in infarct size, behavior, or optical intrinsic signal maps in the first 7 days after stroke, mice treated chronically with memantine showed significant improvements in motor control, measured by cylinder test and grid-walking performance, compared with vehicle-treated animals. Optical intrinsic signal revealed an increased area of forepaw sensory maps at 28 days after stroke. There was decreased reactive astrogliosis and increased vascular density around the infarcted cortex. Peri-infarct Western blots revealed increased brain-derived neurotrophic factor and phosphorylated-tropomyosin-related kinase-B receptor expression.
Our results suggest that memantine improves stroke outcomes in an apparently non-neuroprotective manner involving increased brain-derived neurotrophic factor signaling, reduced reactive astrogliosis, and improved vascularization, associated with improved recovery of sensory and motor cortical function. The clinical availability and tolerability of memantine make it an attractive candidate for clinical translation.
中风治疗受到治疗窗口期有限和具有临床疗效的药物的限制。然而，动物和临床数据表明，中风后存在相当大的可塑性，这可能允许使用恢复调节药物进行治疗。美金刚是一种在临床上广泛用于治疗阿尔茨海默病的 NMDA 谷氨酸受体拮抗剂。
在光血栓性中风后超过 2 小时开始，通过饮用含有 30mg/kg/天美金刚或载体的水进行慢性给药。
尽管在中风后 7 天内，梗死面积、行为或光激内信号图没有差异，但与载体处理的动物相比，长期接受美金刚治疗的小鼠在运动控制方面表现出显著改善，这通过圆筒试验和网格行走性能来衡量。光激内信号显示，中风后 28 天，前爪感觉图的面积增加。梗死皮质周围的反应性星形胶质细胞减少，血管密度增加。梗死周围的 Western 印迹显示脑源性神经营养因子和磷酸化原肌球蛋白相关激酶 B 受体表达增加。
我们的结果表明，美金刚以一种明显非神经保护的方式改善中风结局，涉及增加脑源性神经营养因子信号、减少反应性星形胶质细胞和改善血管化，与感觉和运动皮质功能的恢复改善相关。美金刚的临床可用性和耐受性使其成为临床转化的有吸引力的候选药物。
