Siponimod ameliorates experimental autoimmune neuritis
Abstract Background Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate recepto...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02706-z |
| _version_ | 1797864036875894784 |
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| author | Takafumi Uchi Shingo Konno Hideo Kihara Toshiki Fujioka |
| author_facet | Takafumi Uchi Shingo Konno Hideo Kihara Toshiki Fujioka |
| author_sort | Takafumi Uchi |
| collection | DOAJ |
| description | Abstract Background Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates the maturation, migration, and trafficking of lymphocytes. As of date, the therapeutic effect of sphingosine-1-phosphate receptor (S1PR) agonists on patients with GBS or CIDP remains unclear. Methods To evaluate the effect of siponimod, an agonist of S1PR1 and S1PR5, on experimental autoimmune neuritis (EAN), an animal model of autoimmune peripheral neuropathy, was used. Lewis rats were immunized with 125 μg of synthetic peptide from bovine P2 protein. Rats in the siponimod group were orally administered 1.0 mg/kg siponimod and those in the EAN group were administrated the vehicle on days 5–27 post-immunization (p.i.) daily. The symptom severity was recorded daily. The changes in the expression of cytokines and transcription factors in the lymph nodes and cauda equina (CE) which correlate with the pathogenesis of EAN and recovery of injured nerve were measured using reverse transcription quantitative PCR. Histological study of CE was also performed. Results Flaccid paralysis developed on day 11 p.i. in both groups. Siponimod relieved the symptom severity and decreased the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE compared with that in the EAN group. The expression of Jun proto-oncogene (c-Jun) mRNA increased from the peak to the recovery phase and that of Sonic hedgehog signaling molecule (Shh) and Glial cell line-derived neurotrophic factor (Gdnf) increased prior to increase in c-Jun with no difference observed between the two groups. Histologically, siponimod also reduced demyelinating lesions and inflammatory cell invasion in CE. Conclusions Siponimod has a potential to ameliorate EAN. Shh and Gdnf, as well as C-Jun played a significant role during the recovery of injured nerves. |
| first_indexed | 2024-04-09T22:45:10Z |
| format | Article |
| id | doaj.art-af46bac88af24d4ba6691114d17a4c5e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-09T22:45:10Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-af46bac88af24d4ba6691114d17a4c5e2023-03-22T11:55:10ZengBMCJournal of Neuroinflammation1742-20942023-02-0120111310.1186/s12974-023-02706-zSiponimod ameliorates experimental autoimmune neuritisTakafumi Uchi0Shingo Konno1Hideo Kihara2Toshiki Fujioka3Division of Neurology, Department of Internal Medicine, Toho University Graduate School of MedicineDivision of Neurology, Department of Internal Medicine, Toho University Graduate School of MedicineDivision of Neurology, Department of Internal Medicine, Toho University Graduate School of MedicineDivision of Neurology, Department of Internal Medicine, Toho University Graduate School of MedicineAbstract Background Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates the maturation, migration, and trafficking of lymphocytes. As of date, the therapeutic effect of sphingosine-1-phosphate receptor (S1PR) agonists on patients with GBS or CIDP remains unclear. Methods To evaluate the effect of siponimod, an agonist of S1PR1 and S1PR5, on experimental autoimmune neuritis (EAN), an animal model of autoimmune peripheral neuropathy, was used. Lewis rats were immunized with 125 μg of synthetic peptide from bovine P2 protein. Rats in the siponimod group were orally administered 1.0 mg/kg siponimod and those in the EAN group were administrated the vehicle on days 5–27 post-immunization (p.i.) daily. The symptom severity was recorded daily. The changes in the expression of cytokines and transcription factors in the lymph nodes and cauda equina (CE) which correlate with the pathogenesis of EAN and recovery of injured nerve were measured using reverse transcription quantitative PCR. Histological study of CE was also performed. Results Flaccid paralysis developed on day 11 p.i. in both groups. Siponimod relieved the symptom severity and decreased the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE compared with that in the EAN group. The expression of Jun proto-oncogene (c-Jun) mRNA increased from the peak to the recovery phase and that of Sonic hedgehog signaling molecule (Shh) and Glial cell line-derived neurotrophic factor (Gdnf) increased prior to increase in c-Jun with no difference observed between the two groups. Histologically, siponimod also reduced demyelinating lesions and inflammatory cell invasion in CE. Conclusions Siponimod has a potential to ameliorate EAN. Shh and Gdnf, as well as C-Jun played a significant role during the recovery of injured nerves.https://doi.org/10.1186/s12974-023-02706-zGuillain–Barré syndromeChronic inflammatory demyelinating polyneuropathyExperimental autoimmune neuritisSiponimodS1PR1S1PR5 |
| spellingShingle | Takafumi Uchi Shingo Konno Hideo Kihara Toshiki Fujioka Siponimod ameliorates experimental autoimmune neuritis Journal of Neuroinflammation Guillain–Barré syndrome Chronic inflammatory demyelinating polyneuropathy Experimental autoimmune neuritis Siponimod S1PR1 S1PR5 |
| title | Siponimod ameliorates experimental autoimmune neuritis |
| title_full | Siponimod ameliorates experimental autoimmune neuritis |
| title_fullStr | Siponimod ameliorates experimental autoimmune neuritis |
| title_full_unstemmed | Siponimod ameliorates experimental autoimmune neuritis |
| title_short | Siponimod ameliorates experimental autoimmune neuritis |
| title_sort | siponimod ameliorates experimental autoimmune neuritis |
| topic | Guillain–Barré syndrome Chronic inflammatory demyelinating polyneuropathy Experimental autoimmune neuritis Siponimod S1PR1 S1PR5 |
| url | https://doi.org/10.1186/s12974-023-02706-z |
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