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.

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

“…* vs control, # vs 3NP, @ vs Vilda using one-way ANOVA followed by Tukey's post hoc test; p < 0.05. 3NP; 3-nitropropionic acid, Vilda; vildagliptin, WM; wortmannin against neuronal degeneration in experimental models of PD, multiple sclerosis, and AD [41][42][43]. In the current study, the concurrence of reduced striatal GLP-1 along with striatal damage and neuronal loss, indicated by strong GFAP expression and Nissl staining, provides the first direct evidence for a role of declined striatal GLP-1 level/signaling in 3NP pathology.…”

Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System

“…The signaling axis of GLP-1 and its receptor is critical in the pathogenesis of EAE [6,7]. To test the immune modulation of dulaglutide, a GLP-1 RA, in autoimmune encephalomyelitis, we immunized C57BL/6 mice with MOG 35–55 /CFA (complete Freund’s adjuvant) emulsion and pertussis toxin to induce EAE.…”

“…Since the GLP-1 receptor is expressed throughout the brain, GLP-1 RA is considered to have neurotrophic and anti-inflammation effects for CNS diseases [2,3,4,5,6]. Quite recently, it has been proved that the administration of GLP-1 RA delays the disease onset of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by dampening the effects of oxidative stress [7]. Consistently, activation of GLP-1 receptor signaling attenuates the clinical severity and incidence of EAE, partially via the inactivation of NF-κB signaling in spinal cord and microglia cells [8].…”

Anxiety, Depression, and the Microbiome: A Role for Gut Peptides

“…Moreover, anxiety-like behavior in diabetic mice was blunted by a GLP-1 receptor agonist [247,248], whereas in nondiabetic animals, the impact of a GLP-1 receptor agonist was less clear in reducing anxiety-like behavior [249][250][251]. However, chronic systemic stimulation of GLP-1 receptors promoted antidepressant-like effects in rodents, coupled with increasing hippocampal neurogenesis, suggesting plasticity-related effects could underpin such effects [252][253][254][255]. Furthermore, a GLP-1 receptor agonist was able to reverse LPS-induced depressive-like behavior without directly affecting inflammatory cytokines [256].…”