Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.
We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd...
| Main Authors: | , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2014
|
| _version_ | 1797084808461942784 |
|---|---|
| author | Anthony, D Sibson, N Losey, P Meier, D Leppert, D |
| author_facet | Anthony, D Sibson, N Losey, P Meier, D Leppert, D |
| author_sort | Anthony, D |
| collection | OXFORD |
| description | We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI). During DTH lesion formation, fingolimod reduced BBB breakdown (52%; p = 0.05), and lymphocyte (53%; p = 0.016) and macrophage/activated microglia (49%; p = 0.002) recruitment to the DTH lesion compared with vehicle-treated controls. Following DTH lesion establishment, fingolimod reduced the area of BBB breakdown (75%; p = 0.04), lymphocyte recruitment to the DTH lesion (41%; p = 0.01) and activated microglia outside of the lesion core (p = 0.01), but did not reduce recruitment of macrophages/activated microglia within the DTH lesion. During the chronic disease phase, when the BBB was resealed, fingolimod reduced the area of demyelination by 43% (p = 0.019) compared with vehicle-treated controls, while not affecting lymphocyte recruitment within the lesion. Fingolimod had different beneficial effects during different stages of DTH, reducing BBB breakdown and lesion development/brain tissue damage whilst reducing lymphocyte recruitment when BBB breakdown was apparent, but reducing demyelination independent of lymphocyte infiltration behind an intact BBB. These results suggest a direct CNS effect of fingolimod in this model. |
| first_indexed | 2024-03-07T02:00:15Z |
| format | Journal article |
| id | oxford-uuid:9d1ff7a1-4269-446a-8b5d-29a38d84f6b3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:00:15Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:9d1ff7a1-4269-446a-8b5d-29a38d84f6b32022-03-27T00:40:42ZInvestigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9d1ff7a1-4269-446a-8b5d-29a38d84f6b3EnglishSymplectic Elements at Oxford2014Anthony, DSibson, NLosey, PMeier, DLeppert, DWe examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI). During DTH lesion formation, fingolimod reduced BBB breakdown (52%; p = 0.05), and lymphocyte (53%; p = 0.016) and macrophage/activated microglia (49%; p = 0.002) recruitment to the DTH lesion compared with vehicle-treated controls. Following DTH lesion establishment, fingolimod reduced the area of BBB breakdown (75%; p = 0.04), lymphocyte recruitment to the DTH lesion (41%; p = 0.01) and activated microglia outside of the lesion core (p = 0.01), but did not reduce recruitment of macrophages/activated microglia within the DTH lesion. During the chronic disease phase, when the BBB was resealed, fingolimod reduced the area of demyelination by 43% (p = 0.019) compared with vehicle-treated controls, while not affecting lymphocyte recruitment within the lesion. Fingolimod had different beneficial effects during different stages of DTH, reducing BBB breakdown and lesion development/brain tissue damage whilst reducing lymphocyte recruitment when BBB breakdown was apparent, but reducing demyelination independent of lymphocyte infiltration behind an intact BBB. These results suggest a direct CNS effect of fingolimod in this model. |
| spellingShingle | Anthony, D Sibson, N Losey, P Meier, D Leppert, D Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title | Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title_full | Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title_fullStr | Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title_full_unstemmed | Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title_short | Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. |
| title_sort | investigation of immune and cns mediated effects of fingolimod in the focal delayed type hypersensitivity multiple sclerosis model |
| work_keys_str_mv | AT anthonyd investigationofimmuneandcnsmediatedeffectsoffingolimodinthefocaldelayedtypehypersensitivitymultiplesclerosismodel AT sibsonn investigationofimmuneandcnsmediatedeffectsoffingolimodinthefocaldelayedtypehypersensitivitymultiplesclerosismodel AT loseyp investigationofimmuneandcnsmediatedeffectsoffingolimodinthefocaldelayedtypehypersensitivitymultiplesclerosismodel AT meierd investigationofimmuneandcnsmediatedeffectsoffingolimodinthefocaldelayedtypehypersensitivitymultiplesclerosismodel AT leppertd investigationofimmuneandcnsmediatedeffectsoffingolimodinthefocaldelayedtypehypersensitivitymultiplesclerosismodel |