期刊
NEUROPHARMACOLOGY
卷 79, 期 -, 页码 534-541出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2013.12.022
关键词
Blood-brain barrier; Central nervous system; Delayed-type hypersensitivity model; Fingolimod; Lesion; Multiple sclerosis
资金
- Novartis Pharma AG, Basel, Switzerland
- University of Oxford
- MRC [G0401438] Funding Source: UKRI
- Cancer Research UK [16945] Funding Source: researchfish
- Medical Research Council [G0401438] Funding Source: researchfish
We examined the effect of fingolimod (0.1 and 03 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. (C) 2014 Elsevier Ltd. All rights reserved.
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