Abstract Details

Title The Sphingosine 1-Phosphate Receptor Subtype-1 Is the Primary Target of Fingolimod in the CNS: Interruption of the Pro-inflammatory S1P-S1P1 Cascade

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 145

Objective

Background BACKGROUND: Increased levels of S1P in the cerebrospinal fluid of patients with multiple sclerosis (MS) are directly proportional to expanded disability status scale (EDSS) score. Further, S1P receptor expression is up-regulated in many inflammatory conditions, including the MS brain. These data suggest a critical role of pro-inflammarory S1P-S1P receptor signaling in MS.

Design/Methods DESIGN/METHODS: Brain homogenates/membranes were prepared from untreated and fingolimod-treated rats (0.3 mg/kg/day) by centrifugation. S1P receptor expression and down-modulation of receptor protein was determined using western blots, [sup3][sup3]P-S1P binding assays and receptor subtype-specific compounds. Brain penetration of fingolimod was confirmed by autoradiography and HPLC.

Results RESULTS: Fingolimod and its active metabolite, fingolimod-P, were detectable in brain and spinal cord, reaching high nM levels. [sup3][sup3]P-S1P effectively bound to brain tissue from untreated but not from fingolimod-treated animals. Binding of [sup3][sup3]P-S1P was completely blunted by unlabeled S1P1-specific antagonists (NIBR-0213), indicating a major involvement of S1P1 in S1P-binding. Accordingly, high levels of S1P1 receptor protein were detectable in the brain of untreated animals, but levels were reduced by >70% in fingolimod-treated rats. After drug withdrawal, brain S1P1 levels recovered to normal within 5 weeks.

Conclusions CONCLUSIONS: The data show that in the brain, S1P1 is the dominant S1P receptor subtype that binds pro-inflammatory S1P. Fingolimod treatment down-modulates S1P1 in a reversible manner, and therefore may reduce excessive S1P-S1P1-signaling, possibly breaking the pro-inflammatory cascade through a direct action on neural cells. This mechanism may contribute to the anti-inflammatory effect of fingolimod in the brain of patients with MS, demonstrated by the significant decrease in the number of inflammatory markers on brain magnetic resonance imaging in recent clinical trials.

Authors/Disclosures
Volker Brinkmann, PhD (Novartis Institutes for BioMedical Research) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
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	No disclosure on file
Christopher C. LaGanke, MD (North Central Neurology Associates, PC)	Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sanofi. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Novartis. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GSK. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Serono EMD. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TG Therapeutics.
	No disclosure on file
Norbert Goebels, MD (Heinrich-Heine-University)	Dr. Goebels has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Goebels has received research support from Sanofi-Genzyme.
Marc Bigaud	Marc Bigaud has received personal compensation for serving as an employee of Novartis Pharma.
	No disclosure on file
	No disclosure on file

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