2-BFI 通过选择性地作用于含 NR2B 的 NMDA 受体来预防缺血性中风。

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research Pub Date : 2024-10-16 DOI:10.1016/j.brainres.2024.149284

Shasha Xu , Jiaou Chen , Chunfei Xu , Ye Xu , Lu Xu , Meiqi Zhao , Tong Xu , Yungang Cao , Peijun Li , Zhao Han

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引用次数: 0

摘要

背景和目的：NMDA 受体，特别是含有 NR2A 或 NR2B 亚基的 NMDA 受体，在缺血性中风病理中起着错综复杂的作用，因此有必要进行有针对性的治疗研究。基于我们之前发现的咪唑啉 I2 受体配体 2-（苯并呋喃-2-基）-2-咪唑啉（2-BFI）在缺血性中风期间抑制 NMDA 受体电流的神经保护潜力，本研究旨在阐明 2-BFI 对含有 NR2A 和 NR2B 的 NMDARs 的具体影响：通过全细胞贴片钳技术，我们观察到 2-BFI 对含 NR2A 的 NMDAR 电流（IC50 = 238.6 μM）和含 NR2B 的 NMDAR 电流（IC50 = 18.47 μM）的抑制作用。用表达外源受体亚基的 HEK293 细胞进行的实验显示，2-BFI 对含 NR2B 的 NMDAR 的亲和力明显更高。体内研究包括在瞬时大脑中动脉闭塞（tMCAO）的大鼠体内同时给药 2-BFI 和 NR2A 亚基拮抗剂 NVP-AAM077。主要结果 2-BFI 对抑制含 NR2B 的 NMDAR 电流有明显的偏好，因此在 tMCAO 大鼠模型中与 NVP-AAM077 同时给药可显著减轻脑缺血损伤。此外，还观察到含 NR2B 的 NMDA 受体特异性下游蛋白的表达发生了变化，这表明其具有靶向分子效应。结论和意义本研究揭示了 2-BFI 通过选择性抑制含 NR2B 的 NMDA 受体对缺血性中风的神经保护潜力。这些发现为精确治疗策略奠定了基础，展示了 NR2A 和 NR2B 亚基的不同作用，为缺血性中风治疗的靶向干预铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

2-BFI protects against ischemic stroke by selectively acting on NR2B-containing NMDA receptors

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2-BFI protects against ischemic stroke by selectively acting on NR2B-containing NMDA receptors

Background and purpose

The intricate roles of NMDA receptors, specifically those containing the NR2A or NR2B subunit, in ischemic stroke pathology necessitate targeted therapeutic investigations. Building on our prior discovery showcasing the neuroprotective potential of 2-(benzofuran-2-yl)-2-imidazoline (2-BFI), an imidazoline I2 receptor ligand, in inhibiting NMDA receptor currents during ischemic stroke, this study aims to elucidate the specific impact of 2-BFI on NR2A- and NR2B-containing NMDARs.

Experimental approach

Through whole-cell patch-clamp techniques, we observed an inhibition by 2-BFI on NR2A-containing NMDAR currents (IC50 = 238.6 μM) and NR2B-containing NMDAR currents (IC50 = 18.47 μM). Experiments with HEK293 cells expressing exogenous receptor subunits revealed a significantly higher affinity of 2-BFI towards NR2B-containing NMDARs. In vivo studies involved the co-administration of 2-BFI and the NR2A subunit antagonist NVP-AAM077 in rats subjected to transient middle cerebral artery occlusion (tMCAO).

Key results

2-BFI exhibited a pronounced preference for inhibiting NR2B-containing NMDAR currents, leading to a notable mitigation of cerebral ischemic injury when administered in conjunction with NVP-AAM077 in the tMCAO rat model. Furthermore, alterations in the expression of downstream proteins specific to NR2B-containing NMDA receptors were observed, suggesting targeted molecular effects.

Conclusion and implications

This study unveils the neuroprotective potential of 2-BFI in ischemic stroke by selectively inhibiting NR2B-containing NMDA receptors. These findings lay the foundation for precise therapeutic strategies, showcasing the differential roles of NR2A and NR2B subunits and paving the way for advancements in targeted interventions for ischemic stroke treatment.

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来源期刊

Brain Research 医学-神经科学

CiteScore

5.90

自引率

3.40%

发文量

268

审稿时长

47 days

期刊介绍： An international multidisciplinary journal devoted to fundamental research in the brain sciences. Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed. With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.