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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.

Original publication

DOI

10.1016/j.neuropharm.2013.12.022

Type

Journal article

Journal

Neuropharmacology

Publication Date

04/2014

Volume

79

Pages

534 - 541

Keywords

Blood–brain barrier, Central nervous system, Delayed-type hypersensitivity model, Fingolimod, Lesion, Multiple sclerosis, Animals, Blood-Brain Barrier, Brain, Capillary Permeability, Disease Models, Animal, Disease Progression, Fingolimod Hydrochloride, Immunosuppressive Agents, Lymphocytes, Macrophages, Male, Microglia, Multiple Sclerosis, Propylene Glycols, Rats, Rats, Inbred Lew, Sphingosine