Contributions
Abstract: P874
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 and promyelinating effects of siponimod in the central nervous system (CNS) of experimental autoimmune encephalomyelitis (EAE) mice that are independent of peripheral immune effects. Stimulation of brain-derived neurotrophic factor (BDNF) release by astrocytes and/or 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 association between siponimod treatment and changes in BDNF levels of EAE mice.
Methods: EAE was induced in C57BL/6 mice via immunisation with complete Freund's adjuvant containing MOG1-125 protein and pertussis toxin on Days 0 and 2. Oral siponimod treatment (3 mg/kg/d) was initiated at the peak of the disease (i.e. 14 days after immunisation) and was maintained for approximately 2 months.
Results: Siponimod treatment, initiated at the peak of the disease, progressively reduced EAE symptoms with an overall 30% significant improvement compared with vehicle control at 2 months post immunisation. Within the first week of treatment, siponimod showed an acute 2- to 3-fold increase in BDNF levels in the CNS, mainly measurable in the midbrain. This effect weakened slowly during the following weeks but reoccurred during the last two weeks of treatment, with a 10- to 15-fold increase in BDNF levels versus control. For comparison, when fingolimod (1 mg/kg/d) was tested in similar conditions, although it elicited a similar acute and transient increase in BDNF levels in defined brain areas within the first week of treatment, no difference in BDNF levels was observed at termination compared with control.
Conclusions: These observations suggest a unique potential for siponimod to induce long-term release of neurotrophic BDNF in the midbrain of EAE mice. Follow-up studies are ongoing to fully understand the reasons for the spatiotemporal differences compared with fingolimod-treated EAE mice and to assess its translational relevance in the context of progressing multiple sclerosis.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland. All authors are employees of Novartis Pharma AG.
Abstract: P874
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 and promyelinating effects of siponimod in the central nervous system (CNS) of experimental autoimmune encephalomyelitis (EAE) mice that are independent of peripheral immune effects. Stimulation of brain-derived neurotrophic factor (BDNF) release by astrocytes and/or 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 association between siponimod treatment and changes in BDNF levels of EAE mice.
Methods: EAE was induced in C57BL/6 mice via immunisation with complete Freund's adjuvant containing MOG1-125 protein and pertussis toxin on Days 0 and 2. Oral siponimod treatment (3 mg/kg/d) was initiated at the peak of the disease (i.e. 14 days after immunisation) and was maintained for approximately 2 months.
Results: Siponimod treatment, initiated at the peak of the disease, progressively reduced EAE symptoms with an overall 30% significant improvement compared with vehicle control at 2 months post immunisation. Within the first week of treatment, siponimod showed an acute 2- to 3-fold increase in BDNF levels in the CNS, mainly measurable in the midbrain. This effect weakened slowly during the following weeks but reoccurred during the last two weeks of treatment, with a 10- to 15-fold increase in BDNF levels versus control. For comparison, when fingolimod (1 mg/kg/d) was tested in similar conditions, although it elicited a similar acute and transient increase in BDNF levels in defined brain areas within the first week of treatment, no difference in BDNF levels was observed at termination compared with control.
Conclusions: These observations suggest a unique potential for siponimod to induce long-term release of neurotrophic BDNF in the midbrain of EAE mice. Follow-up studies are ongoing to fully understand the reasons for the spatiotemporal differences compared with fingolimod-treated EAE mice and to assess its translational relevance in the context of progressing multiple sclerosis.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland. All authors are employees of Novartis Pharma AG.