Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphat...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14209 |
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| author | Alicia Weier Michael Enders Philipp Kirchner Arif Ekici Marc Bigaud Christopher Kapitza Jürgen Wörl Stefanie Kuerten |
| author_facet | Alicia Weier Michael Enders Philipp Kirchner Arif Ekici Marc Bigaud Christopher Kapitza Jürgen Wörl Stefanie Kuerten |
| author_sort | Alicia Weier |
| collection | DOAJ |
| description | Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphate receptor modulator siponimod is the only approved drug for SPMS. In the pivotal trial, siponimod reduced disease progression and brain atrophy compared with placebo. The enteric nervous system (ENS) was recently identified as an additional autoimmune target in MS. We investigated the effects of siponimod on the ENS and CNS in the experimental autoimmune encephalomyelitis model of MS. Mice with late-stage disease were treated with siponimod, fingolimod, or sham. The clinical disease was monitored daily, and treatment success was verified using mass spectrometry and flow cytometry, which revealed peripheral lymphopenia in siponimod- and fingolimod-treated mice. We evaluated the mRNA expression, ultrastructure, and histopathology of the ENS and CNS. Single-cell RNA sequencing revealed an upregulation of proinflammatory genes in spinal cord astrocytes and ependymal cells in siponimod-treated mice. However, differences in CNS and ENS histopathology and ultrastructural pathology between the treatment groups were absent. Thus, our data suggest that siponimod and fingolimod act on the peripheral immune system and do not have pronounced direct neuroprotective effects. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:54Z |
| publishDate | 2022-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a8dc27c281bd44a9ad0b4d874f72b2752023-11-24T08:40:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221420910.3390/ijms232214209Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune EncephalomyelitisAlicia Weier0Michael Enders1Philipp Kirchner2Arif Ekici3Marc Bigaud4Christopher Kapitza5Jürgen Wörl6Stefanie Kuerten7Institute of Neuroanatomy, Medical Faculty, University of Bonn, 53115 Bonn, GermanyInstitute of Neuroanatomy, Medical Faculty, University of Bonn, 53115 Bonn, GermanyInstitute of Pathology, University of Bern, CH-3008 Bern, SwitzerlandInstitute of Human Genetics, University Clinic Erlangen, 91054 Erlangen, GermanyNovartis Institutes for BioMedical Research, CH-4002 Basel, SwitzerlandInstitute of Anatomy and Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyInstitute of Anatomy and Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, GermanyInstitute of Neuroanatomy, Medical Faculty, University of Bonn, 53115 Bonn, GermanyMultiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphate receptor modulator siponimod is the only approved drug for SPMS. In the pivotal trial, siponimod reduced disease progression and brain atrophy compared with placebo. The enteric nervous system (ENS) was recently identified as an additional autoimmune target in MS. We investigated the effects of siponimod on the ENS and CNS in the experimental autoimmune encephalomyelitis model of MS. Mice with late-stage disease were treated with siponimod, fingolimod, or sham. The clinical disease was monitored daily, and treatment success was verified using mass spectrometry and flow cytometry, which revealed peripheral lymphopenia in siponimod- and fingolimod-treated mice. We evaluated the mRNA expression, ultrastructure, and histopathology of the ENS and CNS. Single-cell RNA sequencing revealed an upregulation of proinflammatory genes in spinal cord astrocytes and ependymal cells in siponimod-treated mice. However, differences in CNS and ENS histopathology and ultrastructural pathology between the treatment groups were absent. Thus, our data suggest that siponimod and fingolimod act on the peripheral immune system and do not have pronounced direct neuroprotective effects.https://www.mdpi.com/1422-0067/23/22/14209central nervous systementeric nervous systemexperimental autoimmune encephalomyelitisfingolimodmultiple sclerosissiponimod |
| spellingShingle | Alicia Weier Michael Enders Philipp Kirchner Arif Ekici Marc Bigaud Christopher Kapitza Jürgen Wörl Stefanie Kuerten Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis International Journal of Molecular Sciences central nervous system enteric nervous system experimental autoimmune encephalomyelitis fingolimod multiple sclerosis siponimod |
| title | Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis |
| title_full | Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis |
| title_fullStr | Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis |
| title_full_unstemmed | Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis |
| title_short | Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis |
| title_sort | impact of siponimod on enteric and central nervous system pathology in late stage experimental autoimmune encephalomyelitis |
| topic | central nervous system enteric nervous system experimental autoimmune encephalomyelitis fingolimod multiple sclerosis siponimod |
| url | https://www.mdpi.com/1422-0067/23/22/14209 |
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