Contributions
Abstract: EP1582
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Siponimod is a potent, oral, selective sphingosine 1-phosphate (S1P1,5) receptor modulator. Recent preclinical data suggest direct neuroprotective effects of siponimod in the central nervous system that are independent of peripheral immune effects. Stimulation of brain-derived neurotrophic factor (BDNF) synthesis by neurons has been proposed as one of the potential underlying mechanisms for the central effects of the reference S1P1/3/4/5 modulator, fingolimod.
Objective: To investigate the effects of siponimod on BDNF expression in cortical neuronal cultures and in naïve healthy mice.
Methods: Cortical neuronal cultures were stimulated with siponimod or phospho-fingolimod (100 nM) at different concentrations. Extracellular signal-regulated kinase (ERK1/2) phosphorylation was analysed after 30 minutes and the changes in the BDNF levels were analysed after 24 hours incubation with the study compounds. The effect of siponimod on BDNF expression was also analysed in vivo. C57BL/6 (naïve healthy) mice of 6-7 weeks of age were treated daily (intraperitoneal [i.p.] administration) for 14 days with siponimod, fingolimod, AUY954 (a S1P1 selective agonist), NIBR213 (a S1P1 selective antagonist) or saline. Changes in BDNF levels in the cortex, hippocampus, striatum and cerebellum regions of the brain were determined by the ELISA techinique.
Results: The addition of siponimod to the cortical neuronal cultures led to an increase in BDNF levels and ERK1/2 phosphorylation. These observations were further confirmed in the in vivo study. After 14 days of i.p. administration of siponimod, increased levels of BDNF were observed in the cortex, hippocampus and striatum regions but no effect was observed in the cerebellum. Similar results were obtained with AUY954 and fingolimod treatment whereas NIBR213, the S1P1 selective antagonist, had no effect on BDNF levels in any of the brain regions.
Conclusions: These data show that siponimod stimulates BDNF synthesis in certain brain regions, including the cortex and thus support the direct central effects of siponimod in MS. This effect is at least in part mediated by the S1P1 agonism.
Disclosure: The study was funded by Novartis Pharma AG, Basel, Switzerland. Anna Schubart is an employee of Novartis Pharma AG. Ruben Deogracias: nothing to disclose. Yves-Alain Barde: nothing to disclose.
Abstract: EP1582
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Siponimod is a potent, oral, selective sphingosine 1-phosphate (S1P1,5) receptor modulator. Recent preclinical data suggest direct neuroprotective effects of siponimod in the central nervous system that are independent of peripheral immune effects. Stimulation of brain-derived neurotrophic factor (BDNF) synthesis by neurons has been proposed as one of the potential underlying mechanisms for the central effects of the reference S1P1/3/4/5 modulator, fingolimod.
Objective: To investigate the effects of siponimod on BDNF expression in cortical neuronal cultures and in naïve healthy mice.
Methods: Cortical neuronal cultures were stimulated with siponimod or phospho-fingolimod (100 nM) at different concentrations. Extracellular signal-regulated kinase (ERK1/2) phosphorylation was analysed after 30 minutes and the changes in the BDNF levels were analysed after 24 hours incubation with the study compounds. The effect of siponimod on BDNF expression was also analysed in vivo. C57BL/6 (naïve healthy) mice of 6-7 weeks of age were treated daily (intraperitoneal [i.p.] administration) for 14 days with siponimod, fingolimod, AUY954 (a S1P1 selective agonist), NIBR213 (a S1P1 selective antagonist) or saline. Changes in BDNF levels in the cortex, hippocampus, striatum and cerebellum regions of the brain were determined by the ELISA techinique.
Results: The addition of siponimod to the cortical neuronal cultures led to an increase in BDNF levels and ERK1/2 phosphorylation. These observations were further confirmed in the in vivo study. After 14 days of i.p. administration of siponimod, increased levels of BDNF were observed in the cortex, hippocampus and striatum regions but no effect was observed in the cerebellum. Similar results were obtained with AUY954 and fingolimod treatment whereas NIBR213, the S1P1 selective antagonist, had no effect on BDNF levels in any of the brain regions.
Conclusions: These data show that siponimod stimulates BDNF synthesis in certain brain regions, including the cortex and thus support the direct central effects of siponimod in MS. This effect is at least in part mediated by the S1P1 agonism.
Disclosure: The study was funded by Novartis Pharma AG, Basel, Switzerland. Anna Schubart is an employee of Novartis Pharma AG. Ruben Deogracias: nothing to disclose. Yves-Alain Barde: nothing to disclose.