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

Abstract

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.

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

“…These results are in accordance with our previous observations, which showed that also short-term liraglutide treatment rescued ganglion cell density in Wfs1 KO rats (Seppa et al, 2019). Additionally, we found a consistent reduction of axonal area and number of axons in the optic nerve of Wfs1 deficient rats, accompanied by neuropathological signs of degeneration, ultimately resulting in optic nerve atrophy (Plaas et al, 2017;Seppa et al, 2019Seppa et al, , 2021. In the current study, we observed that the treatment with liraglutide was able to halt this neurodegeneration.…”

“…Wfs1 KO rats develop a more prominent diabetic phenotype than any previously generated mouse model of WS and show neurodegeneration of the brainstem and optic nerve. As such, this rat model of WS recapitulates clinical findings observed in human patients and therefore provides an excellent model to evaluate pharmacological treatment strategies (Plaas et al, 2017;Seppa et al, 2019Seppa et al, , 2021Toots et al, 2018).…”

“…To measure visual acuity, a virtual optomotor task (OptoMotry©, Cerebral Mechanics Inc) was used and the test was performed as described previously (Seppa et al, 2021). Shortly, animas were placed in the center of a virtual rotating cylinder displaying vertical bars.…”

“…We have revealed that Wfs1 KO rats display clear degenerative processes in ophthalmic system and late intervention with liraglutide. Treatment of 9-month-old animals can maintain already reduced visual acuity by delaying the progression of optic nerve atrophy and potentially regenerating effect of optic nerve fibres (Plaas et al, 2017;Seppa et al, 2021). Here, our aim was to investigate if life-long treatment with liraglutide can protect Wfs1 KO animals from vision loss.…”

“…Previous studies revealed GLP1 receptor agonists (GLP1 RA) to be effective in restoration of glucose control in genetic mouse (Kondo et al, 2018;Sedman et al, 2016) and rat (Toots et al, 2018) models of WS. Moreover, treatment with the GLP1 RA liraglutide provided neuroprotective and anti-inflammatory effects in old Wfs1 KO rats by restricting the progression of optic nerve atrophy and reducing glial activation (Seppa et al, 2019(Seppa et al, , 2021.…”