Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Boettiger, Gregor and Stadelmann, Christine and Shirvanchi, Kian and von Au, Laureen and Bhushan, Sudhanshu and Wallendszus, Natascha and Schunin, Darja and Westbrock, Victor and Liebisch, Gerhard and Erguen, Sueleyman and Karnati, Srikanth and Berghoff, Martin (2023) The small molecule fibroblast growth factor receptor inhibitor infigratinib exerts anti-inflammatory effects and remyelination in a model of multiple sclerosis. BRITISH JOURNAL OF PHARMACOLOGY, 180 (23). pp. 2989-3007. ISSN 0007-1188, 1476-5381
Full text not available from this repository. (Request a copy)Abstract
Background and PurposeFibroblast 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 ApproachThe 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 ResultsAdministration 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 ImplicationsThis 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CEREBROSPINAL-FLUID; CONCISE GUIDE; CELLS; CNS; LYSOPHOSPHATIDYLCHOLINE; MYELINATION; DETERMINANT; PATHOLOGY; PATHWAY; Experimental autoimmune encephalomyelitis; FGFR; infigratinib; multiple sclerosis; neuroinflammation; remyelination |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2024 14:01 |
| Last Modified: | 19 Mar 2024 14:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60357 |
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