Abstract Details

Title Pharmacological inhibition of FGFR by infigratinib reduces lipids associated with neurodegeneration in MOG35-55-induced EAE

Topic Multiple Sclerosis

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-014

Objective To characterize the effects of pharmacological FGFR inhibition on lipids associated with neurodegeneration in EAE.

Background Analysis of human brain tissue has shown that FGF and FGFR modulate the pathogenesis of multiple sclerosis (MS). Expression of lipids associated with neuronal degeneration is changed in the CSF of patients. The lipids, ceramide and LPC are associated with axonal damage, demyelination, and vascular leakage. Clinical trials have found that FGF-based drugs have beneficial effects on the lipid metabolism. We hypothesized that pharmacological FGFR inhibition reduces the expression of lipids in EAE.

Design/Methods The selective FGFR inhibitor infigratinib (30 mg/kg) was administered orally over 10 days either from the time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment) in MOG_35-55-induced EAE. At the peak of disease (days 18-20 p.i.) and the chronic phase of EAE (days 41-42 p.i.) lipids were analyzed by electrospray ionization-tandem mass spectrometry (ESI-MS), and myelin proteins by western blot in the spinal cord.

Results In the prevention experiment, application of infigratinib resulted in a reduction of LPC (p = 0.05) and ceramide concentrations (p = 0.01), and increased the expression of CNPase, MBP and PLP (p = 0.01) in the chronic phase. No effects on these lipids or myelin proteins were observed in the acute phase. In the suppression experiment, administration of infigratinib did not affect the concentrations of LPC or ceramide. The expression of MBP and PLP was upregulated in the acute phase (p = 0.01).

Conclusions

Pharmacological inhibition of FGFR from the time of EAE induction resulted in a downregulation of lipids associated with neurodegeneration and enhanced myelin protein expression in the chronic phase of EAE, where neurodegeneration prevails. The underlying mechanisms of inhibition mediated lipid alterations are unclear. Inhibition of FGFR may have the potential to reduce lipid-associated neurodegeneration in EAE and MS.

Authors/Disclosures
Martin Berghoff, MD, FAAN (BundeswehrZentralkrankenhaus Koblenz) PRESENTER	Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MerckSerono. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb.
	No disclosure on file
Vinothkumar Rajendran (Justus-Liebig University)	Mr. Rajendran has nothing to disclose.
	No disclosure on file
Srikanth Karnati	No disclosure on file
Ranjithkumar Rajendran (Justus Liebig University)	Mr. Rajendran has nothing to disclose.

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