Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5–8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

BackgroundWolfram syndrome (WS), also known as a DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, Optic nerve Atrophy and Deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 ( WFS1 ) gene. Previous studies revealed that glucagonlike peptide-1 receptor agonist (GLP1 RA) anti-diabetic drugs are effective in delaying and restoring glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats, reducing neuroinflammation, retinal ganglion cell death and optic nerve degeneration. WS is an early-onset, chronical condition and, therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression in WS patients. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide (0.4mg/kg/day) up to the age of 18 months and changes in diabetes markers, visual acuity, hearing sensitivity were monitored in vivo over the course of the 16-month treatment period. ResultsEarly and chronic (16-month) intervention with the GLP-1 RA liraglutide delayed the development of glucose intolerance in WS rats. At the end of the experiment, 91% of saline- and 55% of liraglutide-treated WS rats needed daily insulin supplementation. Liraglutide administration was effective in maintaining visual acuity in WS rats by stalling the progression of cataract, degeneration of retinal ganglion cells and of optic nerve atrophy. Prolonged liraglutide therapy could not prevent sensorineural hearing loss at low frequencies. ConclusionThe rat model of WS used in this study is an excellent predictive model for preclinical trials as it closely recapitulates the relative onset and severity of the main symptoms of WS observed in human patients. We found that a 16-month treatment with GLP1 receptor agonist liraglutide delays or prevents the onset of diabetes and protects against vision loss in a rat model of Wolfram syndrome. Therefore, early diagnosis and prophylactic treatment with the GLP-1R agonist liraglutide may also prove to be a promising treatment option for Wolfram syndrome patients by increasing the quality of life of WS patients.