title: bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury.
abstract: Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI-induced blood-brain barrier (BBB) breakdown. Exogenous basic fibroblast growth factor (bFGF) has been shown to have neuroprotective function in brain injury. The present study therefore investigates the beneficial effects of bFGF on the BBB after TBI and the underlying mechanisms. In this study, we demonstrate that bFGF reduces neurofunctional deficits and preserves BBB integrity in a mouse model of TBI. bFGF suppresses RhoA and upregulates tight junction proteins, thereby mitigating BBB breakdown. In vitro, bFGF exerts a protective effect on BBB by upregulating tight junction proteins claudin-5, occludin, zonula occludens-1, p120-catenin, and β-catenin under oxygen glucose deprivation/reoxygenation (OGD) in human brain microvascular endothelial cells (HBMECs). Both the in vivo and in vitro effects are related to the activation of the downstream signaling pathway, PI3K/Akt/Rac-1. Inhibition of the PI3K/Akt or Rac-1 by specific inhibitors LY294002 or si-Rac-1, respectively, partially reduces the protective effect of bFGF on BBB integrity. Overall, our results indicate that the protective role of bFGF on BBB involves the regulation of tight junction proteins and RhoA in the TBI model and OGD-induced HBMECs injury, and that activation of the PI3K/Akt /Rac-1 signaling pathway underlies these effects.
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Zhou-Guang
authors.initials: ZG
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.|Department of Pharmacy, Longyou People's Hospital, Quzhou, 324400, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Xi-Chong
authors.initials: XC
authors.lastname: Yu
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Ye
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Xia
authors.affiliation: Department of Bioengineering and the McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Noah R
authors.initials: NR
authors.lastname: Johnson
authors.affiliation: Department of Neurosurgery, Cixi People's Hospital, Wenzhou Medical University, Ningbo, 315300, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Emergency, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Da-Qing
authors.initials: DQ
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.affiliation: Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Fu
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China. st_hyz@126.com.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China. xfxj2000@126.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000293:injuries / Q000473:pathology*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D016222:Fibroblast Growth Factor 2; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D005947:Glucose; D010100:Oxygen
keywords: Blood-brain barrier; PI3K/Akt /Rac-1; RhoA; Tight junction; Traumatic brain injury; bFGF