30 research outputs found
FGF/FGFR pathways in multiple sclerosis and in its disease models
No full textMultiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS
‐induced EAE through ERK and Akt signalling
No full textFibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2) was achieved by application of tamoxifen; EAE was induced using the MOG peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2 mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2 mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2 mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2 mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2 mice than controls. Fgfr2ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS
Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes
No full textFibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS
Anti‐inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis
No full textAbstract Background and Purpose FGF, VEGFR‐2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG 35‐55 ‐induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi‐kinase inhibition of FGFR1‐3, CSFR and VEGFR‐2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model. Experimental Approach Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg −1 ) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42). Key Results In the prevention experiment, treatment with 6.25 or 12.5 mg·kg −1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg −1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long‐lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches. Conclusion and Implications Multi‐kinase inhibition by fexagratinib in a well‐tolerated dose of 1 mg·kg −1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients
The small molecule fibroblast growth factor receptor inhibitor infigratinib exerts anti‐inflammatory effects and remyelination in a model of multiple sclerosis
No full textAbstract Background and Purpose Fibroblast growth factors and receptors (FGFR) have been shown to modulate inflammation and neurodegeneration in multiple sclerosis (MS). The selective FGFR inhibitor infigratinib has been shown to be effective in cancer models. Here, we investigate the effects of infigratinib on prevention and suppression of first clinical episodes of myelin oligodendrocyte glycoprotein (MOG) 35–55 ‐induced experimental autoimmune encephalomyelitis (EAE) in mice. Experimental Approach The FGFR inhibitor infigratinib was given over 10 days from the time of experimental autoimmune encephalomyelitis induction or the onset of symptoms. The effects of infigratinib on proliferation, cytotoxicity and FGFR signalling proteins were studied in lymphocyte cell lines and microglial cells. Key Results Administration of infigratinib prevented by 40% and inhibited by 65% first clinical episodes of the induced experimental autoimmune encephalomyelitis. In the spinal cord, infiltration of lymphocytes and macrophages/microglia, destruction of myelin and axons were reduced by infigratinib. Infigratinib enhanced the maturation of oligodendrocytes and increased remyelination. In addition, infigratinib resulted in an increase of myelin proteins and a decrease in remyelination inhibitors. Further, lipids associated with neurodegeneration such as lysophosphatidylcholine and ceramide were decreased as were proliferation of T cells and microglial cells. Conclusion and Implications This proof of concept study demonstrates the therapeutic potential of targeting FGFRs in a disease model of multiple sclerosis. Application of oral infigratinib resulted in anti‐inflammatory and remyelinating effects. Thus, infigratinib may have the potential to slow disease progression or even to improve the disabling symptoms of multiple sclerosis
Bewertung des Fibroblasten-Wachstumsfaktor-Rezeptors FGFR1 bei experimenteller autoimmuner Enzephalomyelitis (EAE)
No full textFibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). Recent studies on the function of FGF2 in MOG35-55-induced experimental autoimmune encephalitis (EAE) showed that systemic deletion of FGF2 leads to a more severe disease course, increased lymphocyte and macrophage infiltration and decreased remyelination. In the present study the in vivo function of the corresponding receptor Fgfr1 was characterized using an oligodendrocyte-specific genetic approach. Plp/CreERT:Fgfr1fl/fl mice were administered tamoxifen to induce conditional Fgfr1 deletion in oligodendrocytes (referred to as Fgfr1ind-/-). In MOG35-55-induced EAE the Fgfr1ind-/- mice show a delayed onset of disease, less maximum disease severity and enhanced recovery. Decreased lymphocyte and macrophage/microglia infiltration, and myelin and axon degeneration are found in Fgfr1ind-/- mice. In acute EAE downregulation of proinflammatory cytokines such as TNF-alpha, IL-1beta and IL-6, in chronic EAE downregulation of the CX3CL1/CX3CR1 pathway is seen in Fgfr1ind-/- mice. Furthermore, increased expression of BDNF, TrkB (neurotrophic tyrosine kinase receptor, type 2) and decreased expression of Lingo-1 are found in Fgfr1ind-/- mice. Fgfr1 ablation in oligodendrocytes showed increased TrkB expression in whole lysate of cortex and spinal cord. These data suggest that impaired signalling via oligodendroglial Fgfr1 has a beneficial effect on MOG35-55-induced EAE. These findings on the oligodendroglial Fgfr1 pathway may offer a new target for developing therapy in multiple sclerosis
Oligodendrocyte-specific deletion of FGFR2 ameliorates MOG35-55-induced EAE through ERK and Akt signalling
No full textPharmacological inhibition of FGFR by infigratinib reduces lipids associated with neurodegeneration in MOG35-55-induced EAE (P2-3.014)
No full textOligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE
No full textMultiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/− mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/− mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS
