The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis

Cohan, Stanley; Benedict, Ralph H. B.; Cree, Bruce A.C.; DeLuca, John; Hua, Le H.; Chun, Jerold

doi:10.1007/s40263-022-00927-z

Cited by 23 publications

(14 citation statements)

References 114 publications

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“…The immunomodulatory properties of siponimod impair the autoreactive lymphocytes egress from the lymph nodes and thus prevent their infiltration into the CNS and reduce inflammation 22 . In addition, siponimod could cross the blood–brain barrier (BBB) and exhibit neuroprotective effects in various preclinical models by directly interacting with the CNS‐resident cells 23–25 . We recently showed that siponimod treatment exerted neuroprotection against glaucoma injury.…”

Section: Introductionmentioning

confidence: 99%

“…22 In addition, siponimod could cross the blood-brain barrier (BBB) and exhibit neuroprotective effects in various preclinical models by directly interacting with the CNS-resident cells. [23][24][25] We recently showed that siponimod treatment exerted neuroprotection against glaucoma injury. Further, the study revealed that neuronal S1PR1 ablation enhanced neuronal degeneration and siponimod mediates its protective effects through neuronal S1PR1 in experimental glaucoma.…”

Section: Introductionmentioning

confidence: 99%

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S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

et al. 2022

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Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1‐phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1/2 activation and attenuated the apoptotic signaling via suppression of c‐Jun/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt/Erk1/2 activation, c‐Jun/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c‐Jun/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

et al. 2022

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“…However, apart from diffusion, active mechanisms such as receptor-mediated transport exist for drug uptake into the CNS [79]. Siponimod targets both S1P1 and S 1 P 5 receptors on BBB endothelial cells [80], which might contribute to an active transport into the brain. Inhibition of S1P1 receptors, specifically in endothelial cells, results in a transient opening of the BBB [81].…”

Section: Discussionmentioning

confidence: 99%

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

Starke¹,

Millward²,

Prinz³

et al. 2023

Theranostics

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Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging ( 19 F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation. Here we investigated siponimod, a sphingosine 1-phosphate (S1P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo 19 F MR imaging of a disease modifying drug. Methods: The 19 F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for 19 F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired 19 F MR spectra and images in vivo directly after administration, and in ex vivo tissues. Results: The 19 F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue. Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver. Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs. In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum. No secondary 19 F signals were detected from metabolites. From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution. Conclusion: Siponimod can be imaged non-invasively using 19 F UTE MRI in the form administered to MS patients, without modification. This study lays the groundwork for more extensive preclinical and clinical investigations. With the necessary technical development, 19 F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology.

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“…Additionally, activation of LPA 2 in situ in the heart by using appropriate methods such as gene therapy or specific agonist, combined with an appropriate delivery modality, might provide other options to reduce the pro-tumorigenic concerns. S1P 1 , which is also a lysophospholipid receptor and highly homologous to the LPA receptor family, has been shown to maintain endothelial function and vascular patency, and with the use of the S1P1 agonist FTY720, no obvious adverse events were found in small-scale human trials, 54 and is a proven drug target through S1P receptor modulators that now include 4 FDA-approved medicines, 55,56 supporting the possibility of cardiac therapeutics targeting LPA 2 .…”

Section: Pei Etmentioning

confidence: 99%

LPA ₂ Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction

Pei

Cai

Wang

et al. 2022

Circulation Research

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Rationale: Myocardial infarction (MI) is one of the most dangerous adverse cardiovascular events. Our previous study found that lysophosphatidic acid (LPA) is increased in human peripheral blood after MI, and LPA has a protective effect on the survival and proliferation of various cell types. However, the role of LPA and its receptors in MI is less understood. Objectives: To study the unknown role of LPA and its receptors in heart during MI. Methods and Results: In this study, we found that mice also had elevated LPA level in peripheral blood, as well as increased cardiac expression of its receptor LPA 2 in the early stages after MI. With adult and neonate MI models in global Lpar2 knockout ( Lpar2 -KO) mice, we found Lpar2 deficiency increased vascular leak leading to disruption of its homeostasis, so as to impaired heart function and increased early mortality. Histological examination revealed larger scar size, increased fibrosis, and reduced vascular density in the heart of Lpar2 -KO mice. Furthermore, Lpar2 -KO also attenuated blood flow recovery after femoral artery ligation with decreased vascular density in gastrocnemius. Our study revealed that Lpar2 was mainly expressed and altered in cardiac endothelial cells during MI, and use of endothelial-specific Lpar2 knockout mice phenocopied the global knockout mice. Additionally, adenovirus- Lpar2 and pharmacologically activated LPA 2 significantly improved heart function, reduced scar size, increased vascular formation, and alleviated early mortality by maintaining vascular homeostasis owing to protecting vessels from leakage. Mechanistic studies demonstrated that LPA-LPA 2 signaling could promote endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk pathway and enhanced endothelial cell tube formation via PKD1-CD36 signaling. Conclusions: Our results indicate that endothelial LPA-LPA 2 signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA 2 signal might have clinical therapeutic potential to protect the heart from ischemic injury.

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The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis

Cited by 23 publications

References 114 publications

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

LPA ₂ Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction

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The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis

Cited by 23 publications

References 114 publications

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod

LPA 2 Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction

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LPA ₂ Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction