Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

Journal article

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.

Authors: Anthony, D; Sibson, N; Losey, P; Meier, D; Leppert, D

• Publication status: Published
• Journal: Neuropharmacology
• Volume: 79
• Pages: 534-541
• Publication date: 2014-04-01
• DOI: 10.1016/j.neuropharm.2013.12.022
• EISSN: 1873-7064
• ISSN: 0028-3908
• Language: English
• Keywords: Macrophages; Disease Progression; Disease Models, Animal; Rats; Rats, Inbred Lew; Immunosuppressive Agents; Lymphocytes; Sphingosine; Brain; Multiple Sclerosis; Propylene Glycols; Animals; Microglia; Male; Blood-Brain Barrier; Capillary Permeability