Abstract
Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, in children and young adults (Maiti et al, 2019; Fouda et al, 2020)
The following primary antibodies were applied in this study: anti-p-GSK3β, anti-GSK3β, anti-p-JNK, anti-JNK, anti-p-NFκB and anti-NFκB antibodies purchased from Cell Signaling Technology (Danvers, MA, United States); antiFGF20, anti-VE-cadherin, anti-Claudin-5, and anti-GFAP antibodies obtained from Abcam (Cambridge, MA, United States); and anti-p-AKT, anti-AKT and anti-Occludin antibodies purchased from Invitrogen (Carlsbad, CA, United States) and Santa Cruz Biotechnology (Dallas, TX, United States), respectively
We evaluated whether the effects of recombinant human FGF20 (rhFGF20) on tumor necrosis factor-α (TNF-α)-induced blood-brain barrier (BBB) injury were mediated by the AKT/GSK3β pathway
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, in children and young adults (Maiti et al, 2019; Fouda et al, 2020). Primary damage occurs at the moment of trauma (Loane and Faden, 2010), while secondary damage occurs subsequently, including excitotoxicity, blood-brain barrier (BBB) disruption, oxidative stress, neuroinflammation, ischemia, edema, etc. Among these processes, BBB disruption partially mediated by inflammation is a vital mechanism contributing to the progression of brain injury and long-term neurological deficits (Shi et al, 2015). TJ and AJ proteins, including Claudin, Occludin, Zonula Occluders (ZO) and VE-cadherin, play major roles in limiting paracellular diffusion between ECs and maintaining the integrity of the BBB (Jiao et al, 2011; Zhang et al, 2020). A drug targeting BBB integrity and the inflammatory response is a potential therapeutic strategy for TBI
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