FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

Wang, Xue; Hu, Jian; Du, Jingting; Dordoe, Confidence; Zhou, Qiulin; Huang, Wenting; Guo, Ruili; Han, Fanyi; Guo, Kaiming; Ye, Shasha; Lin, Li; Li, Xiaokun

doi:10.3389/fphar.2020.590669

Cited by 14 publications

(15 citation statements)

References 78 publications

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“…*p < 0.05 vs. TBI+vehicle (1 mg/kg BSA). Chen et al, 2020). In the first set of experiments in TBI mice, we tested dose-range effects of rA2 administration given at 2 h after TBI in BBB integrity disruption examined with the commonly used Evans blue extravasation assay.…”

Section: Discussionmentioning

confidence: 99%

“…As early BBB breakdown results in increased vascular permeability, cerebral edema, inflammation, and neuronal cell death after TBI, the acute phase of BBB damage occupied a central place in TBI pathophysiology ( Shlosberg et al, 2010 ). Therefore, resealing of the early BBB leakage is critical for attenuation of secondary brain injury, and has been proposed as a therapeutic intervention approach for treating TBI ( Shlosberg et al, 2010 ; Chen et al, 2020 ). In the first set of experiments in TBI mice, we tested dose-range effects of rA2 administration given at 2 h after TBI in BBB integrity disruption examined with the commonly used Evans blue extravasation assay.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

et al. 2021

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Microvascular failure is one of the key pathogenic factors in the dynamic pathological evolution after traumatic brain injury (TBI). Our laboratory and others previously reported that Annexin A2 functions in blood-brain barrier (BBB) development and cerebral angiogenesis, and recombinant human Annexin A2 (rA2) protected against hypoxia plus IL-1β-induced cerebral trans-endothelial permeability in vitro, and cerebral angiogenesis impairment of AXNA2 knock-out mice in vivo. We thereby hypothesized that ANXA2 might be a cerebrovascular therapy candidate that targets early BBB integrity disruption, and subacute/delayed cerebrovascular remodeling after TBI, ultimately improve neurological outcomes. In a controlled cortex impact (CCI) mice model, we found rA2 treatment (1 mg/kg) significantly reduced early BBB disruption at 24 h after TBI; and rA2 daily treatment for 7 days augmented TBI-induced mRNA levels of pro-angiogenic and endothelial-derived trophic factors in cerebral microvessels. In cultured human brain microvascular endothelial cells (HBMEC), through MAPKs array, we identified that rA2 significantly activated Akt, ERK, and CREB, and the activated CREB might be responsible for the rA2-induced VEGF and BDNF expression. Moreover, rA2 administration significantly increased cerebral angiogenesis examined at 14 days and vessel density at 28 days after TBI in mice. Consistently, our results validated that rA2 significantly induced angiogenesis in vitro, evidenced by tube formation and scratched migration assays in HBMEC. Lastly, we demonstrated that rA2 improved long-term sensorimotor and cognitive function, and reduced brain tissue loss at 28 days after TBI. Our findings suggest that rA2 might be a novel vascular targeting approach for treating TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

et al. 2021

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“…Rota-rod test was carried out to assess the limb motor coordination and balance of mice on the automated rota-rod (San Diego Instruments, San Diego, CA, USA), as shown in previous study [ 36 ]. Mice in each group were trained for three consecutive days before TBI induction.…”

Section: Methodsmentioning

confidence: 99%

“…Grip strength test was performed to measure the forelimb muscles grip strength by a grid grip strength meter (San Diego Instruments). Each mouse was pulled backward by its tail until it released its grip [ 32 , 36 ]. Each animal was trained before TBI induction and then tested three times on days 1 and 3 after TBI.…”

Section: Methodsmentioning

confidence: 99%

Hydroxychloroquine attenuates neuroinflammation following traumatic brain injury by regulating the TLR4/NF-κB signaling pathway

Wang

Chen

et al. 2022

J Neuroinflammation

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Background After traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood–brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway. Methods C57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated. Results HCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ. Conclusions HCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

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“…The mixture of FGF1 and fibrin glue (a slowrelease carrier and adhesive agent) in the CNS when applied topically after injury reduced the cerebral infarction, protects cortical cells from loss and reduce microglia penetration thereby promoting a recovery system (Tsai et al, 2015). Treatment with FGF1 preceded in ischemia preserved BBB integrity by regulating tight junctions and adherens junctions' expressions (Cheng et al, 2011;Chen et al, 2020). In addition, brain cells with FGF1 exhibited protective effects by upregulating tight junction proteins and inhibiting RhoA through PI3K-Akt-Rac1 pathway regulation to protect the BBB (Wu et al, 2017).…”

Section: Fibroblast Growth Factors In the Treatment Of Stroke Fgf1 In Strokementioning

confidence: 99%

Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke

et al. 2021

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Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.

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FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

Cited by 14 publications

References 78 publications

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

Hydroxychloroquine attenuates neuroinflammation following traumatic brain injury by regulating the TLR4/NF-κB signaling pathway

Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke

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