首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration
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The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration

机译:间接NMDAR拮抗剂阿坎酸可诱导与持续性神经保护和神经再生有关的缺血后神经系统恢复

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摘要

Cerebral ischemia stimulates N-methyl-D-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.
机译:脑缺血会刺激N-甲基-D-天冬氨酸受体(NMDARs),导致钙浓度和兴奋性毒性增加。然而,由于不良的临床前研究设计或NMDAR拮抗剂的毒性,NMDAR的失活在临床研究中失败了。阿坎酸是一种用于慢性酒精依赖患者的间接NMDAR拮抗剂。我们在这里分析了阿坎酸对脑损伤,神经系统恢复及其潜在机制的治疗潜力。将小鼠暴露于脑缺血,用阿坎酸或盐水腹腔注射治疗(对照),并存活至3个月。当在卒中后不迟于12小时给予Acamprosate时,可产生持续的神经保护作用并增加神经系统恢复。后者与缺血后血管生成的增加有关,尽管阿坎酸不刺激血管生成本身。而是,血管生成的增加是由于抑制了钙蛋白酶介导的前伤害性信号传导级联反应。因此,阿坎酸介导的钙蛋白酶活性降低导致p35的降解降低,生存因子STAT6的丰度增加以及N端Jun激酶活化降低。钙蛋白酶的抑制与血脑屏障的稳定性增强,氧化应激的降低和脑白细胞浸润有关。考虑到其优异的耐受性,对神经系统恢复,脑组织存活和神经重构的持续影响,阿坎酸是未来辅助中风治疗的诱人候选物。

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