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

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.

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

Scientific Reports ◽

10.1038/s41598-019-52295-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

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.

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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 ◽

10.3390/cells10113193 ◽

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.

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Liraglutide, 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model

Scientific Reports ◽

10.1038/s41598-021-81768-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kadri Seppa ◽

Toomas Jagomäe ◽

Kaia Grete Kukker ◽

Riin Reimets ◽

Marko Pastak ◽

...

Keyword(s):

Optic Nerve ◽

Cognitive Decline ◽

Rat Model ◽

Treatment Effect ◽

Wolfram Syndrome ◽

Wild Type ◽

Optic Nerve Atrophy ◽

Loss Of Vision ◽

Improved Learning ◽

First Time

AbstractWolfram 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.

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Valproate promotes survival of retinal ganglion cells in a rat model of optic nerve crush

Neuroscience ◽

10.1016/j.neuroscience.2012.07.056 ◽

2012 ◽

Vol 224 ◽

pp. 282-293 ◽

Cited By ~ 31

Author(s):

Z.Z. Zhang ◽

Y.Y. Gong ◽

Y.H. Shi ◽

W. Zhang ◽

X.H. Qin ◽

...

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Rat Model ◽

Ganglion Cells ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush

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CMT2A Harboring Mitofusin 2 Mutation with Optic Nerve Atrophy and Normal Visual Acuity

International Medical Case Reports Journal ◽

10.2147/imcrj.s237620 ◽

2020 ◽

Vol Volume 13 ◽

pp. 41-45

Author(s):

Silvana Guerriero ◽

Francesco D'Oria ◽

Giacomo Rossetti ◽

Rosa Anna Favale ◽

Stefano Zoccolella ◽

...

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Optic Nerve Atrophy ◽

Mitofusin 2 ◽

Normal Visual Acuity

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Bilateral Syphilitic Optic Neuropathy with Secondary Autoimmune Optic Neuropathy and Poor Visual Outcome

Case Reports in Ophthalmology ◽

10.1159/000496142 ◽

2019 ◽

Vol 10 (1) ◽

pp. 81-88 ◽

Cited By ~ 1

Author(s):

Tanya Kowalski ◽

Dujon Fuzzard ◽

Isla Williams ◽

Jonathan Darby ◽

Heather Gwen Mack

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Optic Neuropathy ◽

Nerve Palsy ◽

Visual Loss ◽

Visual Outcome ◽

High Dose ◽

Optic Nerve Atrophy ◽

Poor Visual Outcome ◽

Appropriate Treatment

We describe the case of a 65-year-old man who suffered progressive visual loss despite appropriate treatment of ocular syphilis. Our patient initially presented with a unilateral 6th nerve palsy and associated double vision, which self-resolved over 6 months. His ophthalmic examination was otherwise normal. 12 months after the initial complaint, he represented with dyschromatopsia, reduced visual acuity, tonic pupils, and optic nerve atrophy. He tested positive for syphilis and was admitted for treatment of neurosyphilis with high-dose benzylpenicillin. Despite treatment, at a 4-month review his visual acuity remained poor and progression of optic nerve atrophy was noted alongside the development of bilateral central scotomas. Further testing was congruent with a diagnosis of autoimmune optic retinopathy. We propose this to be secondary to his syphilitic infection. Syphilis is known as the “great mimicker,” and despite being quite treatable, this case highlights ongoing complexity in the diagnosis and management of syphilis, unfortunately with a poor visual outcome.

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Valproic acid attenuates inflammation of optic nerve and apoptosis of retinal ganglion cells in a rat model of optic neuritis

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.11.066 ◽

2017 ◽

Vol 96 ◽

pp. 1363-1370 ◽

Cited By ~ 6

Author(s):

Qiang Liu ◽

Haining Li ◽

Juan Yang ◽

Xiaoyan Niu ◽

Chunmei Zhao ◽

...

Keyword(s):

Valproic Acid ◽

Optic Nerve ◽

Optic Neuritis ◽

Retinal Ganglion Cells ◽

Rat Model ◽

Ganglion Cells ◽

Retinal Ganglion

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Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration

Scientific Reports ◽

10.1038/s41598-017-09392-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 13

Author(s):

Mario Plaas ◽

Kadri Seppa ◽

Riin Reimets ◽

Toomas Jagomäe ◽

Maarja Toots ◽

...

Keyword(s):

Optic Nerve ◽

Wolfram Syndrome ◽

Insulin Dependent Diabetes ◽

Optic Nerve Atrophy ◽

Insulin Dependent

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Diseases of the eye in chronic alcoholism

Kazan medical journal ◽

10.17816/kmj1780 ◽

2013 ◽

Vol 94 (1) ◽

pp. 101-105

Author(s):

R R Iskhakova ◽

F R Saifullina

Keyword(s):

Visual Acuity ◽

Optic Nerve ◽

Peripheral Vision ◽

Clinical Manifestations ◽

Chronic Alcoholism ◽

Low Grade ◽

Optic Nerve Atrophy ◽

Eye Disorders ◽

Temporal Parts ◽

Late Stages

Chronic alcoholism is a disease affecting all the vital organs, including development of functional and organic eye disorders in 2-70% of cases. Alcoholic (ethanol) amblyopia with such features as slow gradient visual acuity decrease in both eyes (although visual acuity can decrease down do a very low grade, the complete blindness is rare) is among the disorders in patients with chronic alcoholism. Fundus of the eye at the beginning of the disease is normal in most of the cases, sometimes an optic nerve congestion and mild features of optic neuritis can be observed. Sometimes optic nerve hyperemia or anemia can be observed. Simple optic nerve atrophy seen as the temporal parts or the entire disc blanching can be seen at the late stages. Alcohol toxicity can also result as peripheral vision decrease, with degree of it increasing depending on the clinical manifestations of the alcoholism. Generally, eye disorders in patients with chronic alcoholism in most of the cases manifest as central retinal area damage and combination of retinal and optic nerve involvement.

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