scholarly journals Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3193
Author(s):  
Toomas Jagomäe ◽  
Kadri Seppa ◽  
Riin Reimets ◽  
Marko Pastak ◽  
Mihkel Plaas ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Rat Model ◽  
Early Onset ◽  
Receptor Agonist ◽  
Vision Loss ◽  
Blood Glucose Control ◽  
Wolfram Syndrome ◽  
Hearing Sensitivity ◽  
Glucagon Like Peptide 1 ◽  
Wfs1 Gene

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.

scholarly journals Early intervention and lifelong treatment with GLP1 receptor agonist liraglutide in a Wolfram Syndrome rat model with an emphasis on visual neurodegeneration, sensorineural hearing loss and diabetic phenotype

2021 ◽  
Author(s):  
Toomas Jagomäe ◽  
Kadri Seppa ◽  
Riin Reimets ◽  
Marko Pastak ◽  
Mihkel Plaas ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Hearing Loss ◽  
Optic Nerve ◽  
Early Diagnosis ◽  
Rat Model ◽  
Early Onset ◽  
Receptor Agonist ◽  
Wolfram Syndrome ◽  
Retinal Ganglion ◽  
Optic Nerve Atrophy

Abstract 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.

scholarly journals GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kadri Seppa ◽  
Maarja Toots ◽  
Riin Reimets ◽  
Toomas Jagomäe ◽  
Tuuliki Koppel ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Optic Nerve ◽  
Rat Model ◽  
Receptor Agonist ◽  
Neurodegenerative Disorder ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Wolfram Syndrome ◽  
Retinal Ganglion ◽  
Knock Out

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.

scholarly journals A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

2017 ◽  
Vol 9 (404) ◽  
pp. eaan0972 ◽  
Author(s):  
Hannah F. Botfield ◽  
Maria S. Uldall ◽  
Connar S. J. Westgate ◽  
James L. Mitchell ◽  
Snorre M. Hagen ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Rat Model ◽  
Receptor Agonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals The glucagon-like peptide 1 receptor agonist liraglutide attenuates placental ischemia-induced hypertension

2020 ◽  
Vol 318 (1) ◽  
pp. H72-H77
Author(s):  
Subhi Talal Younes ◽  
Kenji J. Maeda ◽  
Jennifer Sasser ◽  
Michael J. Ryan
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Function ◽  
Nitric Oxide Synthase ◽  
Rat Model ◽  
Receptor Agonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Oxide Synthase ◽  
Placental Ischemia

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic perturbations of nitric oxide function, reflective of generalized endothelial dysfunction. Therapies that target the nitric oxide pathway have shown promise in both clinical and preclinical studies of preeclampsia. The glucagon-like peptide 1 agonists have been shown to increase nitric oxide and lower blood pressure in patients with diabetes, in part, through activation of nitric oxide synthase (NOS). Therefore, we hypothesized that a direct acting glucagon-like peptide 1 receptor agonist would improve stigmata of the preeclampsia syndrome. Using the reduced uterine perfusion pressure rat model, we found that treatment with liraglutide significantly lowered blood pressure, improved renal function, and upregulated NOS3 protein expression in the mesenteric arterial bed. However, there were adverse effects on pup growth that were likely related to diminished food intake in the dams. Collectively, these data support the premise that the use of drugs that improve NOS abundance, including the glucagon-like peptide 1 agonists, is a rational therapeutic approach to the treatment of preeclampsia, but suggest cautious and careful study of their safety before potential clinical use in humans. NEW & NOTEWORTHY Drugs that target the glucagon-like peptide-1 pathway such as liraglutide are already used clinically, and it has been shown to promote endothelial nitric oxide synthase (NOS3) expression. We demonstrate that liraglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, lowers blood pressure, improves renal function, and upregulates NOS3 in a rat model of placental ischemia. These data suggest that drugs that target the nitric oxide system, including GLP-1R agonists, are a potential therapeutic option for preeclampsia.

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