Excitotoxicity is a major contributor to cell death during the acute phase of ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of memantine, within the range currently used and well tolerated for the treatment of Alzheimer's disease, produce a protective effect in stroke. A coculture preparation exposed to modeled ischemia showed cell death associated with rapid glutamate rises and cytotoxic Ca(2+) influx. Cell death was significantly enhanced in the presence of high memantine concentrations. However, low memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day) memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in stroke lesions that had been separated into either small/striatal or large/striatocortical infarcts. However, higher doses of memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of memantine should be considered for patients 'at risk' of stroke, while higher doses are contraindicated.
展开▼
机译:兴奋性毒性是缺血性中风急性期细胞死亡的主要因素,但积极的药理性兴奋性毒性靶向在临床上已失败。在这里,我们调查了在目前使用的阿尔茨海默氏病耐受性良好的低剂量美金刚预处理中,是否对中风产生保护作用。暴露于模型缺血的共培养物制备显示与谷氨酸快速升高和细胞毒性Ca(2+)大量涌入相关的细胞死亡。在高美金刚浓度下,细胞死亡显着增加。然而,低美金刚浓度可通过兴奋性毒性级联中断来显着保护神经元和神经胶质。在60分钟可逆性局灶性脑缺血之前的24小时开始,全身性地给小鼠施用一定剂量的美金刚剂量(0.02、0.2、2、10和20μmg/ kg /天),并持续48小时的恢复期。低剂量(0.2μmg/ kg /天)美金刚治疗可显着减少已分为小/纹状体或大/纹状体皮层梗死的中风病灶的病灶体积(减少30%至50%)并改善行为预后。但是,较高剂量的美金刚(20μmg/ kg /天)会明显增加伤害。这些结果表明,对于有“中风风险”的患者,应考虑临床确定的低剂量美金刚,而高剂量则是禁忌的。
展开▼