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@ARTICLE{Rehman:273922,
      author       = {Rehman, Rida and Froehlich, Albrecht and Olde Heuvel,
                      Florian and Elsayed, Lobna and Boeckers, Tobias and
                      Huber-Lang, Markus and Morganti-Kossmann, Cristina and
                      Roselli, Francesco},
      title        = {{T}he {FGFR} inhibitor {R}ogaratinib reduces microglia
                      reactivity and synaptic loss in {TBI}.},
      journal      = {Frontiers in immunology},
      volume       = {15},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DZNE-2024-01396},
      pages        = {1443940},
      year         = {2024},
      abstract     = {Traumatic brain injury (TBI) induces an acute reactive
                      state of microglia, which contribute to secondary injury
                      processes through phagocytic activity and release of
                      cytokines. Several receptor tyrosine kinases (RTK) are
                      activated in microglia upon TBI, and their blockade may
                      reduce the acute inflammation and decrease the secondary
                      loss of neurons; thus, RTKs are potential therapeutic
                      targets. We have previously demonstrated that several
                      members of the Fibroblast Growth Factor Receptor (FGFR)
                      family are transiently phosporylated upon TBI; the
                      availability for drug repurposing of FGFR inhibitors makes
                      worthwhile the elucidation of the role of FGFR in the acute
                      phases of the response to TBI and the effect of FGFR
                      inhibition.A closed, blunt, weight-drop mild TBI protocol
                      was employed. The pan-FGFR inhibitor Rogaratinib was
                      administered to mice 30min after the TBI and daily up to 7
                      days post injury. Phosphor-RTK Arrays and proteomic antibody
                      arrays were used to determine target engagement and
                      large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3
                      immunostaining were employed for validation. As outcome
                      parameters of the TBI injury immunostainings for NeuN,
                      VGLUT1, VGAT at 7dpi were considered.Inhibition of FGFR
                      during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4
                      and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was
                      traced back to Iba1+ microglia. Rogaratinib substantially
                      dowregulated the proteomic signature of the
                      neuroimmunological response to trauma, including the
                      expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG.
                      Prolonged Rogaratinib treatment reduced neuronal loss upon
                      TBI and prevented the loss of excitatory (vGLUT+)
                      synapses.The FGFR family is involved in the early induction
                      of reactive microglia in TBI. FGFR inhibition selectively
                      prevented FGFR phosphorylation in the microglia, dampened
                      the overall neuroimmunological response and enhanced the
                      preservation of neuronal and synaptic integrity. Thus, FGFR
                      inhibitors may be relevant targets for drug repurposing
                      aimed at modulating microglial reactivity in TBI.},
      keywords     = {Animals / Microglia: drug effects / Microglia: metabolism /
                      Brain Injuries, Traumatic: drug therapy / Brain Injuries,
                      Traumatic: metabolism / Brain Injuries, Traumatic:
                      immunology / Mice / Male / Synapses: drug effects /
                      Synapses: metabolism / Mice, Inbred C57BL / Phosphorylation:
                      drug effects / Disease Models, Animal / Receptor, Fibroblast
                      Growth Factor, Type 1: antagonists $\&$ inhibitors /
                      Receptor, Fibroblast Growth Factor, Type 1: metabolism /
                      Protein Kinase Inhibitors: pharmacology / Protein Kinase
                      Inhibitors: therapeutic use / proteomics (Other) / reactive
                      microglia (Other) / receptor tyrosine kinase (Other) /
                      synapses (Other) / traumatic brain injury (Other) /
                      Receptor, Fibroblast Growth Factor, Type 1 (NLM Chemicals) /
                      Protein Kinase Inhibitors (NLM Chemicals)},
      cin          = {AG Roselli / AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)1910001 / I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39635532},
      pmc          = {pmc:PMC11614719},
      doi          = {10.3389/fimmu.2024.1443940},
      url          = {https://pub.dzne.de/record/273922},
}