The N-methyl-D-aspartate (NMDA) receptor is a crucial mediator of pathological glutamate-driven excitotoxicity and subsequent neuronal death in acute ischemic stroke. Although the roles of the NMDAR's composite GluN2A-C subunits have been investigated in this phenomenon, the relative importance of the GluN2D subunit has yet to be evaluated. Herein, GluN2D-/- mice were studied in a model of ischemic stroke using MALDI FT-ICR mass spectrometry imaging to investigate the role of the GluN2D subunit of the NMDA receptor in brain ischemia. GluN2D-/- mice underwent middle cerebral artery occlusion (MCAO) and brain tissue was subsequently harvested, frozen, and cryosectioned. Tissue sections were analyzed via MALDI FT-ICR mass spectrometry imaging. MALDI analyses revealed increases in several calcium-related species, namely vitamin D metabolites, LysoPC, and several PS species, in wild-type mouse brain tissue when compared to wild type. In addition, GluN2D-/- mice also displayed an increase in PC, as well as a decrease in DG, suggesting reduced free fatty acid release from brain ischemia. These trends indicate that GluN2D-/- mice show enhanced rates of neurorecovery and neuroprotection from ischemic strokes compared to wild-type mice. The cause of neuroprotection may be the result of an increase in PGP in knockout mice, contributing to greater cardiolipin synthesis and decreased sensitivity to apoptotic signals. Graphical abstract.

中文翻译：

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使用 MALDI MSI 对缺血性中风后 GluN2D-/- 和野生型小鼠进行原位代谢物和脂质分析。

N-甲基-D-天冬氨酸（NMDA）受体是急性缺血性中风中病理性谷氨酸驱动的兴奋性毒性和随后的神经元死亡的关键介质。尽管 NMDAR 复合 GluN2A-C 亚基在这种现象中的作用已得到研究，但 GluN2D 亚基的相对重要性尚未评估。在此，使用 MALDI FT-ICR 质谱成像在缺血性中风模型中研究了 GluN2D-/- 小鼠，以研究 NMDA 受体的 GluN2D 亚基在脑缺血中的作用。GluN2D-/- 小鼠经历大脑中动脉闭塞 (MCAO)，随后收获、冷冻和冷冻切片脑组织。通过 MALDI FT-ICR 质谱成像分析组织切片。MALDI 分析揭示了几种钙相关物种的增加，即维生素 D 代谢物，与野生型相比，野生型小鼠脑组织中的 LysoPC 和几种 PS 物种。此外，GluN2D-/- 小鼠还表现出 PC 增加，以及 DG 减少，表明脑缺血释放的游离脂肪酸减少。这些趋势表明，与野生型小鼠相比，GluN2D-/- 小鼠的缺血性中风的神经恢复率和神经保护作用增强。神经保护的原因可能是基因敲除小鼠 PGP 增加的结果，导致更多的心磷脂合成和降低对凋亡信号的敏感性。图形概要。这些趋势表明，与野生型小鼠相比，GluN2D-/- 小鼠的缺血性中风的神经恢复率和神经保护作用增强。神经保护的原因可能是基因敲除小鼠 PGP 增加的结果，导致更多的心磷脂合成和降低对凋亡信号的敏感性。图形概要。这些趋势表明，与野生型小鼠相比，GluN2D-/- 小鼠的缺血性中风的神经恢复率和神经保护作用增强。神经保护的原因可能是基因敲除小鼠 PGP 增加的结果，导致更多的心磷脂合成和降低对凋亡信号的敏感性。图形概要。