BAF312, also called Siponimod, is a selective, potent and brain-penetrant S1P receptor modulator used to treat multiple sclerosis, with EC50 values of 0.4nM and 5nM for S1P1 and S1P3 in GTPγS binding assay, respectively. Oral administration of 1mg/kg BAF312 markedly reduced peripheral lymphocyte count, a pharmacodynamic biomarker in autoimmune diseases for S1P1 activation, by 88% in Lewis rats at 8h post treatment, with a shorter duration of action than FTY720[1]. BAF312 also showed effect on S1P5 with EC50 of 0.98nM. Treatment with BAF312 at concentration of 1μM for 1h promote internalization of S1P1 receptors in CHO cells expressed myc-tagged human S1P1 receptors. Daily oral administration of BAF312 at dose of 0.3 or 3mg/kg for 24 days dose-dependently suppressed ongoing disease symptoms in rat EAE. BAF312 concentration-dependently activated the GIRK channel via S1P1 in atrial myocytes with EC50 value of 15.8nM[2].
Siponimod/BAF312 at concentrations of 0.1 nM, 0.5 nM, 1.0 nM, and 5.0 nM significantly reduced TNFα-induced apoptosis in hiPSCs-NSCs/NPCs cells, as indicated by decreased green fluorescence from activated caspase-3/7.
Int J Mol Sci. 2024 Feb 20;25(5):2454.
BV2 microglial cells
0.1 µM
1 hour
To assess the effect of Siponimod on the release of IL-6 and RANTES from activated microglial cells. Results showed that Siponimod reduced the release of IL-6 and RANTES from TNF-stimulated BV2 cells.
J Neuroinflammation. 2016 Aug 26;13(1):207.
Rat primary cultured cortical neurons
0.1 nM, 0.5 nM, 1.0 nM
10 days
Siponimod/BAF312 dose-dependently decreased the risk of cortical neuron death with HR 0.84, 0.81, and 0.78 and p values of 0.007, 0.002, and 2×10^-5, respectively.
Int J Mol Sci. 2024 Feb 20;25(5):2454.
Primary rat microglia
10 µM or 50 µM
3 days
To investigate the effects of Siponimod on microglial morphology and actin filament organization in an inflammatory milieu induced by LPS. Results showed that 50 µM Siponimod significantly reduced the LPS-induced increase in mean cell area and altered actin organization.
Int J Mol Sci. 2022 Oct 31;23(21):13278.
Mixed astrocyte/microglia cell cultures
1 µM
60 minutes
To investigate the modulatory effect of Siponimod on proinflammatory responses in mixed glia cell cultures. Results showed that Siponimod did not decrease cytokine release; instead, the concentration of some cytokines (e.g., MCP-1, IL12-p40, G-CSF) was significantly increased.
Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2204509119.
mouse microglia
1 nM, 10 nM, 100 nM, 1 μM
18 h
BAF312 moderately attenuated LPS-induced increases in IL6 levels
J Neuroinflammation. 2016 Feb 8;13:31
human astrocytes
1 nM, 10 nM, 100 nM, 1 μM
BAF312 induced ERK and AKT phosphorylation in a concentration-dependent manner
J Neuroinflammation. 2016 Feb 8;13:31
mouse astrocytes
1 nM, 10 nM, 100 nM, 1 μM
BAF312 induced ERK and AKT phosphorylation in a concentration-dependent manner
J Neuroinflammation. 2016 Feb 8;13:31
Siponimod/辛波莫德 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Experimental autoimmune encephalomyelitis (EAE)
Continuous intracerebroventricular (icv) infusion
0.45 μg/day
4 weeks
To evaluate the neuroprotective effects of Siponimod in the CNS of EAE mice. Results showed that Siponimod improved EAE clinical scores, reduced microgliosis and astrogliosis, decreased lymphocyte infiltration, and rescued GABAergic transmission deficits and PV+ interneuron loss.
J Neuroinflammation. 2016 Aug 26;13(1):207.
C57BL/6 mice
Collagenase VII-S-induced ICH model
Intraperitoneal and subcutaneous injection
1 mg/kg
First dose 30 minutes after surgery, followed by doses at 24 and 48 hours
Siponimod treatment significantly reduced brain lesion volume and brain edema, and improved long-term neurologic function.
Aging Dis. 2023 Jun 1;14(3):966-991
Lewis rats
Experimental autoimmune neuritis (EAN)
Oral
1.0 mg/kg/day
Daily administration from day 5 to 27 post-immunization
To evaluate the therapeutic effect of Siponimod on EAN. Results showed that Siponimod alleviated symptom severity, reduced the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE, and decreased demyelinating lesions and inflammatory cell invasion.
J Neuroinflammation. 2023 Feb 14;20(1):35
Mice
Chronic high intraocular pressure and acute NMDA excitotoxicity models
Oral
10 mg/kg
8 weeks
Siponimod showed neuroprotective effects on the retina and brain in chronic high intraocular pressure and acute NMDA excitotoxicity models, upregulating Akt and Erk1/2 phosphorylation levels through neuronal S1PR1 signaling, and reducing microglial activation and reactive gliosis.
Neural Regen Res. 2023 Apr;18(4):840-848
C57BL/6 mice
NMDA excitotoxicity-induced retinal injury model
Oral
10 mg/kg diet
Continuous administration for 7 days
To evaluate the anti-inflammatory effects of Siponimod in the NMDA excitotoxicity model. Results showed that Siponimod significantly reduced glial activation, suppressed pro-inflammatory pathways, and diminished NLRP3 inflammasome activation and iNOS upregulation.
Mol Neurobiol. 2023 Dec;60(12):7222-7237
Mice
Cuprizone-induced demyelination mouse model
Oral
10 mg/kg food
2 weeks
Siponimod treatment promoted remyelination
Neurol Neuroimmunol Neuroinflamm. 2022 Mar 30;9(3):e1161
New Zealand albino rabbits
Diabetic retinopathy and age-related macular degeneration model
Intravitreal injection
1300 ng or 6500 ng
Single injection, observation time points included 0.5, 1, 2, 4, 6, 8, 10, 16, and 24 hours
To evaluate the pharmacokinetics and toxicity of Siponimod in the vitreous. Results showed that the half-lives of low and high doses of Siponimod were 2.8 h and 3.9 h, respectively, and no signs of toxicity were observed in the retina at 24 h and 7 days.
Mol Pharm. 2024 Jul 1;21(7):3310-3320
Mice
Healthy mice
Oral
133 mg/kg
Single dose
First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod, demonstrating drug distribution in the stomach and liver.
Theranostics. 2023 Feb 5;13(4):1217-1234
C57BL/6J mice
Experimental autoimmune encephalomyelitis (EAE)
Oral
20 mg/kg
Ad libitum for 33 days
Evaluated the effects of siponimod on EAE model, showing peripheral lymphopenia but no significant impact on CNS and ENS histopathology
Int J Mol Sci. 2022 Nov 17;23(22):14209
SJL/J mice
Experimental Autoimmune Encephalomyelitis (EAE) model
Oral gavage
3 mg/kg
Daily administration, starting at day 3, 5, or 8 after adoptive transfer
BAF312 treatment significantly ameliorated clinical EAE and diminished subpial pathology, concomitant with a selective reduction in the capacity of transferred T cells to make Th17 cytokines.
JCI Insight. 2020 Jan 16;5(1):e132522
Mice
Chronic experimental autoimmune encephalomyelitis (EAE) model
Oral gavage
3 mg/kg
Once daily for 30 days
To investigate whether siponimod can inhibit the formation of meningeal ectopic lymphoid tissue (mELT). Results showed that siponimod ameliorated the clinical course of EAE and strongly reduced the extent of mELT.
Neurol Neuroimmunol Neuroinflamm. 2021 Dec 15;9(1):e1117
SJL/J mice
TMEV infection model
Oral gavage
3 mg/kg
Daily until euthanasia
To investigate the effect of Siponimod on TMEV-induced neurodegeneration. Results showed that Siponimod treatment worsened clinical disability score (CDS), decreased body weight (BW) and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Siponimod suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Siponimod- and vehicle-treated animals, but there were differences between HC and TMEV groups, indicating TMEV-induced inflammation contributed to increased spine volume. Spine histology revealed no significant microglial density differences between groups in gray matter, but HC animals had higher type 1 morphology and lower type 2 morphology percentages in gray and white matter regions. This suggests that Siponimod did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord.
Int J Mol Sci. 2023 Aug 20;24(16):12990
C57BL/6 mice
Cuprizone-induced demyelination model
Oral
3.125 mg/kg
Daily administration for 3 weeks
To investigate the protective effects of Siponimod in the cuprizone-induced demyelination model. Results demonstrated that Siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury, and these protective effects were completely absent in S1pr5-deficient mice.
Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2204509119.
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