Design and Evaluation of Lyophilized Fibroblast Growth Factor 21 and Its Protection against Ischemia Cerebral Injury

Yang, Xuanxin; Qi, Hui; Yu, Bingjie; Huang, Zhen; Zhou, Peipei; Wang, Panfeng; Wang, Zhitao; Pang, Shucai; Li, Jinghang; Wang, Hanshi; Lin, Li; Li, Xiaokun; Wang, Xiaojie

doi:10.1021/acs.bioconjchem.7b00588

Cited by 20 publications

(22 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…downregulates ER stress-related protein expression by activating the ERK1/2, PI3K/Akt, and JNK signaling pathways, thus protecting neurons from ischemic injury [44]. Consistent with these findings, we have demonstrated a role for endogenous FGF21 in brain tissue recovery and functional outcome improvement after stroke.…”

Section: Discussionsupporting

confidence: 87%

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

Liu¹,

Wang²,

Zhu³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Fibroblast growth factor 21 (FGF21) is an important neuroprotective factor in the central nervous system (CNS), and it has been reported that FGF21 can protect against cerebral ischemia during the acute phase. However, the possible effects of FGF21 on ischemic brains and the interactions between FGF21 and nonneuronal cells have not been examined. Thus, the aim of this study was to elucidate the protective effects of endogenous FGF21 in ischemic brains.Methods: In this study, in vivo ischemia/reperfusion injury mouse model established by transient middle cerebral artery occlusion (MCAO)/reperfusion and in vitro cell models of oxygen/glucose deprivation (OGD)/reoxygenation (R) were used. Western blot analysis, RT-PCR, double immunofluorescence staining, immunohistochemistry, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, neurobehavioral tests, cell counting kit-8 (CCK-8) assay and high-throughput gene sequencing were employed to explore the mechanism by which FGF21 unleash neuroprotective effort of astrocyte phenotype shifts in ischemic stroke.Results: We found that cortical FGF21 expression significantly increased after MCAO/reperfusion, peaking at 7 d. Ischemia-activated microglia were the main sources of endogenous FGF21 in brain tissue. However, FGF21 deficiency aggravated brain injury and slowed neurological functional recovery in FGF21 knockout mice. The in vitro and vivo studies revealed that FGF21 could activate astrocytes and mediate astrocytic phenotype. FGF21-activated astrocytes contributed to neuronal survival and synaptic protein upregulation after ischemia.Conclusion: Collectively, our data indicate that FGF21 plays vital roles in alleviating ischemic brain by mediating the manifestation of potentially pro-recovery astrocytic phenotypes. Therefore, modulation of FGF21 is a potential target strategy for stroke.

show abstract

Section: Discussionsupporting

confidence: 87%

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

Liu¹,

Wang²,

Zhu³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compared with vehicle treatment, treatment with rhFGF21 has previously been reported to significantly reduce infarct volumes at 24 h after focal ischemia in rats [38]. A similar result was observed in mice at 72 h using 2,3,5-triphenyltetrazolium chloride (TTC) staining (Fig.…”

Section: Rhfgf21 Protects Against Brain Injury In Mcao Micesupporting

confidence: 70%

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

Wang

Liu

Zhu

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

show abstract

“…FGF21 weakly binds heparin and can pass through the blood-brain barrier by simple diffusion (Hsuchou et al, 2007). rhFGF21 has been demonstrated to have potent therapeutic activity in various neurological disorders, such as Parkinson's disease (Makela et al, 2014), Alzheimer's disease (Amiri et al, 2018;Chen et al, 2019), and ischemic stroke Yang X. et al, 2018). In the current study, pretreatment with rhFGF21 at doses of 1.5 and 3.0 mg/kg significantly prevented the increase in immobility time induced by LPS administration in the FST and TST, indicating the antidepressant-like effect of this large molecule.…”

Section: Discussionmentioning

confidence: 99%

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

Wang

Zhu

et al. 2020

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia in vitro. The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-kB (NF-kB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial Frontiers in Pharmacology | www.frontiersin.org February 2020 | Volume 11 | Article 154 1 expression of proinflammatory cytokines through NF-kB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment.

show abstract

Design and Evaluation of Lyophilized Fibroblast Growth Factor 21 and Its Protection against Ischemia Cerebral Injury

Cited by 20 publications

References 40 publications

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

Contact Info

Product

Resources

About