title: Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.
abstract: 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.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Electronic address: daniel.anthony@pharm.ox.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Cancer Research UK (CR-UK), Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, OX3 7DQ Oxford, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Losey
authors.affiliation: Novartis Pharma AG, Kirschgartenstrasse 14, 4051 Basel, Switzerland.
authors.forename: Daniela Piani
authors.initials: DP
authors.lastname: Meier
authors.affiliation: Department of Medicine, University Hospital Basel, Spitalstrasse 21/Petersgraben 4, 4031 Basel, Switzerland; F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Leppert
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Blood–brain barrier; Central nervous system; Delayed-type hypersensitivity model; Fingolimod; Lesion; Multiple sclerosis