Abstract
Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.
Highlights
Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration
This study provides the first evidence of the feasibility of pharmacological treatment for life-threatening neurodegeneration in an aged WS rat model
WS is diagnosed after the onset of metabolic syndrome and the appearance of the first neurodegenerative symptoms, such as loss of vision
Summary
Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. The results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model. Our group has demonstrated in Wfs[1] knock-out (KO) rats that 19-week-long treatment with Glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide decreases ER stress, inflammation, and proliferation www.nature.com/scientificreports in Langerhans islets and thereby prevents or delays the development of a diabetic phenotype[8]. We investigate here if late intervention with GLP-1 receptor agonist liraglutide has a neuroprotective effect and thereby can prevent the progression of inferior olive neurodegeneration in the rat model of WS
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