Although N-methyl-D-aspartate receptor (NMDAR) antagonism has been shown to have a neuroprotective effect in many preclinical stroke models, the efficacy of this antiexcitotoxicity strategy in clinical trials in stroke patients has been disappointing. Interestingly, it has been reported that NMDAR antagonism is not neuroprotective in C57BL/6 mice subjected to distal middle cerebral artery occlusion (dMCAO), supporting the notion that whether these treatments are neuroprotective depends on the type of cerebral ischemia. However, because C57BL/6 mice are inherently resistant to excitotoxicity, the reported lack of neuroprotection could also be explained by the difference in the mouse strain studied rather than the stroke model used. Here we examined the neuroprotective efficacy of NMDAR antagonism in FVB/NJ mice, an excitotoxicity-prone mouse strain, subjected to dMCAO. Although C57BL/6 mice are known to have an excitotoxicity-resistant genetic background and FVB/NJ mice are known to have an excitotoxicity-prone genetic background, the infarct volume and density of neurodegenerating neurons were similar in the two mouse strains following dMCAO. In addition, none of the antiexcitotoxicity agents studied, including the canonical NMDAR antagonist MK801 and the therapeutic peptides Tat-NR2B9c and L-JNKI-1, protected the FVB/NJ mouse brain against ischemic damage induced by dMCAO. In conclusion, our data demonstrated that FVB/NJ mice are no more susceptible to cerebral ischemia than C57BL/6 mice and that NMDAR antagonism is ineffective in mice, even in an excitotoxicity-prone strain, subjected to dMCAO.

中文翻译：

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FVB/NJ 小鼠中，远端大脑中动脉闭塞引起的中风损伤对 N-甲基-D-天冬氨酸受体拮抗作用具有抵抗力。

尽管N-甲基-D-天冬氨酸受体（NMDAR）拮抗作用已被证明在许多临床前卒中模型中具有神经保护作用，但这种抗兴奋性毒性策略在卒中患者临床试验中的疗效却令人失望。有趣的是，据报道，NMDAR 拮抗剂对远端大脑中动脉闭塞 (dMCAO) 的 C57BL/6 小鼠没有神经保护作用，这支持了这些治疗是否具有神经保护作用取决于脑缺血类型的观点。然而，由于 C57BL/6 小鼠本质上对兴奋性毒性具有抵抗力，因此所报道的神经保护作用的缺乏也可以通过所研究的小鼠品系的差异而不是所使用的中风模型来解释。在这里，我们检查了 NMDAR 拮抗剂对 FVB/NJ 小鼠（一种易产生兴奋性毒性的小鼠品系）进行 dMCAO 的神经保护功效。尽管已知 C57BL/6 小鼠具有抗兴奋性毒性遗传背景，而 FVB/NJ 小鼠已知具有易兴奋性毒性遗传背景，但 dMCAO 后两种小鼠品系的梗塞体积和神经退行性神经元密度相似。此外，所研究的抗兴奋性毒性药物，包括经典的 NMDAR 拮抗剂 MK801 和治疗性肽 Tat-NR2B9c 和 L-JNKI-1，均不能保护 FVB/NJ 小鼠大脑免受 dMCAO 引起的缺血性损伤。总之，我们的数据表明，FVB/NJ 小鼠并不比 C57BL/6 小鼠更容易受到脑缺血的影响，并且 NMDAR 拮抗作用在小鼠中无效，即使是在接受 dMCAO 的易兴奋性毒性品系中也是如此。