Abstract
Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization. Positron-Emission tomography (PET) imaging with (R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29 and 34 during normal disease progression, preventive and curative treatments with fingolimod (1 mg/kg/day). Additionally, bodyweight and clinical symptoms were determined. Preventive treatment diminished bodyweight loss and inhibited the appearance of neurological symptoms. In non-treated rats, PET showed that neuroinflammation peaked in the brainstem at day 19, whereas the imaging signal was decreased in cortical regions. Both preventive and curative treatment reduced neuroinflammation in the brainstem at day 19. Eight days after treatment withdrawal, neuroinflammation had flared-up, especially in cortical regions. Preventive treatment with fingolimod suppressed clinical symptoms and neuroinflammation in the brainstem. After treatment withdrawal, clinical symptoms reappeared together with neuroinflammation in cortical regions, suggesting a different pathway of disease progression.
Highlights
Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system characterized by demyelination
EAE rats were monitored for disease progression and fingolimod treatment effects
This effect can be explained by inflammatory-induced cachexia, a common process in all the EAE models, an effect observed previously by our group
Summary
Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system characterized by demyelination. New therapies for MS have focused on suppression of relapses, and the reduction of lesions observed by magnetic resonance imaging (MRI). Fingolimod (FTY720; Gilenya®) was the first oral agent to be approved for treatment of MS. Results from clinical trials have consistently proved an effective decrease in relapse rates, new MRI lesions, disability progression and brain volume loss in patients with relapsingremitting MS (Cohen et al 2010; Kappos et al 2010; Calabresi et al 2014). Fingolimod is a sphingosine-1-phosphate (S1P) analogue that is phosphorylated in vivo and binds as a functional antagonist to all the S1P receptor subtypes, except S1P2 (Brinkmann et al 2002; Cohen and Chun 2011). The S1P receptors are present on lymphocytes and play a key role in lymphocyte trafficking (Graeler and Goetzl 2002, 2004; Lo et al 2005)
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