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.

Autor: Zhang XL; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Du WH; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China., Qian SX; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Lu XD; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Yu X; Department of Neurology, Bengbu Medical College, Bengbu, 233030, China., Fang HL; Department of Neurology, Bengbu Medical College, Bengbu, 233030, China., Dong JL; Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China., Song M; Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China., Sun YY; Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China., Wu XQ; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Shen YF; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Hao YN; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Shen MH; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Zhou BQ; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China., Wang YP; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China. ypwang93@163.com., Xu CY; Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China. xucongying0806@163.com., Jin XC; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China. xinchunjin@gmail.com.; Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. xinchunjin@gmail.com.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Nov; Vol. 45 (11), pp. 2241-2252. Date of Electronic Publication: 2024 Jun 20.
DOI: 10.1038/s41401-024-01323-7
Abstrakt: 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 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/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.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: