title: Effect of Preventive and Curative Fingolimod Treatment Regimens on Microglia Activation and Disease Progression in a Rat Model of Multiple Sclerosis.
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.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: David
authors.identifier: 0000-0003-3308-3167
authors.initials: D
authors.lastname: Vállez García
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
authors.affiliation: Department of Radiology and Oncology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Daniele
authors.initials: D
authors.lastname: de Paula Faria
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Rudi A J O
authors.initials: RAJO
authors.lastname: Dierckx
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. e.f.j.de.vries@umcg.nl.
authors.forename: Erik F J
authors.initials: EFJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D009103:Multiple Sclerosis; D051381:Rats
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
keywords: Experimental autoimmune encephalomyelitis; Fingolimod; Multiple sclerosis; Neuroinflammation; Positron-emission tomography