title: Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats.
abstract: Introduction:Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE).Methods:EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline,n= 6, liraglutide,n= 7). Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined.Results:Liraglutide treatment delayed disease onset (group clinical score significantly >0) by 2 days and markedly reduced disease severity (median clinical score 2 vs. 5;p= 0.0003). Fourteen of 15 (93%) of vehicle-treated rats reached the humane endpoint (clinical score ≥4) by day 11 compared to 5 of 15 (33%) of liraglutide-treated rats (p= 0.0004). Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p< 0.01) and reduced the neurodegenerative marker APP (p= 0.036) in the brain. GFAP levels were not significantly changed with drug treatment (p= 0.09).Conclusion:We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor agonists should be investigated further as a potential therapy for MS.
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Centre of Medical Parasitology, Department of Clinical Microbiology, Copenhagen University HospitalCopenhagen, Denmark.
authors.forename: Brian
authors.initials: B
authors.lastname: DellaValle
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus University Aarhus, Denmark.
authors.forename: Gitte S
authors.initials: GS
authors.lastname: Brix
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Clinical Biochemistry and Department of Clinical Medicine, Aarhus University Hospital, Aarhus UniversityAarhus, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Brock
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Clinical Biochemistry and Department of Clinical Medicine, Aarhus University Hospital, Aarhus UniversityAarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Gejl
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus UniversityAarhus, Denmark; Centre For Functionally Integrative Neuroscience, Aarhus UniversityAarhus, Denmark.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Landau
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus UniversityAarhus, Denmark; Centre For Functionally Integrative Neuroscience, Aarhus UniversityAarhus, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Møller
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus UniversityAarhus, Denmark; Department of Endocrinology, Bispebjerg University HospitalCopenhagen, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Rungby
authors.affiliation: Department of Biomedicine/Pharmacology, Aarhus University Aarhus, Denmark.
authors.forename: Agnete
authors.initials: A
authors.lastname: Larsen
keywords: APP; EAE; GLP-1; MS; MnSOD; liraglutide; multiple sclerosis