Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination
Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phas...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/16/12990 |
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| author | Suyog Pol Ravendra Dhanraj Anissa Taher Mateo Crever Taylor Charbonneau Ferdinand Schweser Michael Dwyer Robert Zivadinov |
| author_facet | Suyog Pol Ravendra Dhanraj Anissa Taher Mateo Crever Taylor Charbonneau Ferdinand Schweser Michael Dwyer Robert Zivadinov |
| author_sort | Suyog Pol |
| collection | DOAJ |
| description | Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp’s impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- 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 Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp’s effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
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| spelling | doaj.art-3b0e8c465e274eab93ed57b92ce9e7e02023-11-19T01:33:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161299010.3390/ijms241612990Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of DemyelinationSuyog Pol0Ravendra Dhanraj1Anissa Taher2Mateo Crever3Taylor Charbonneau4Ferdinand Schweser5Michael Dwyer6Robert Zivadinov7Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USABuffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USASiponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp’s impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- 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 Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp’s effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models.https://www.mdpi.com/1422-0067/24/16/12990TMEVMRIbrain atrophyspinal cordsiponimod |
| spellingShingle | Suyog Pol Ravendra Dhanraj Anissa Taher Mateo Crever Taylor Charbonneau Ferdinand Schweser Michael Dwyer Robert Zivadinov Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination International Journal of Molecular Sciences TMEV MRI brain atrophy spinal cord siponimod |
| title | Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination |
| title_full | Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination |
| title_fullStr | Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination |
| title_full_unstemmed | Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination |
| title_short | Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler’s Murine Encephalomyelitis Virus Model of Demyelination |
| title_sort | effect of siponimod on brain and spinal cord imaging markers of neurodegeneration in the theiler s murine encephalomyelitis virus model of demyelination |
| topic | TMEV MRI brain atrophy spinal cord siponimod |
| url | https://www.mdpi.com/1422-0067/24/16/12990 |
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