首都医科大学金新春等研究人员合作发现，神经胶质生长因子2能通过降低Mfsd2a/窖蛋白1介导的跨细胞通透性和Pdlim5/YAP/TAZ介导的细胞旁通透性，来缓解缺血和再灌注对血脑屏障完整性的损害。这一研究成果于2024年6月20日在线发表在国际学术期刊《中国药理学报》上。

研究人员表示，血脑屏障（BBB）完整性受损是溶栓和血管内治疗后出血转化和血管源性水肿的病理基础。目前临床上还没有获准用于减轻急性缺血性脑卒中（AIS）后血脑屏障损伤的药物。神经胶质生长因子2（GGF2）是神经胶质蛋白-1β的重组版本，可刺激神经胶质细胞的增殖和分化。研究人员之前发现，活化的小胶质细胞和促炎因子可在AIS后破坏BBB。

研究人员揭示了GGF2对AIS诱导的BBB损伤的影响及其潜在机制。研究人员建立了小鼠大脑中动脉闭塞模型：小鼠接受90分钟缺血和22.5小时再灌注（I/R），并在再灌注前接受GGF2（2.5、12.5、50ng/kg，静脉注射）治疗。研究人员发现，GGF2治疗剂量依赖性地减少了I/R诱导的BBB损伤（通过埃文斯蓝（EB）和免疫球蛋白G（IgG）渗漏以及紧密连接蛋白occludin降解检测到）。此外，研究人员还发现，GGF2剂量依赖性地逆转了AIS诱导的囊泡转运增加、窖蛋白1（Cav-1）的上调以及含主要促进剂超家族结构域2a（Mfsd2a）的下调。

此外，GGF2还能降低I/R诱导的PDZ和LIM结构域蛋白5（Pdlim5）的上调，PDZ和LIM结构域蛋白5是一种适配蛋白，在AIS后的BBB损伤中发挥了重要作用。此外，GGF2还能显著缓解I/R引起的YAP和TAZ减少、小胶质细胞活化和炎症因子上调。这些结果表明，GGF2可抑制Mfsd2a/Cav-1介导的跨细胞通透性和Pdlim5/YAP/TAZ介导的细胞旁通透性，从而缓解I/R对BBB完整性的破坏。

附：英文原文

Title: Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability

Author: Zhang, Xiao-ling, Du, Wei-hong, Qian, Shu-xia, Lu, Xu-dong, Yu, Xin, Fang, Hai-lun, Dong, Jia-li, Song, Min, Sun, Yan-yun, Wu, Xiao-qiang, Shen, Yu-fei, Hao, Ya-nan, Shen, Min-hui, Zhou, Bei-qun, Wang, Yan-ping, Xu, Cong-ying, Jin, Xin-chun

Issue&Volume: 2024-06-20

Abstract: The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1β that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

DOI: 10.1038/s41401-024-01323-7

Source: https://www.nature.com/articles/s41401-024-01323-7