The neuroprotective effect of GLP-1 receptor agonist liraglutide in a rat model of Wolfram syndrome
Date
2021-07-02
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Abstract
Wolframi sündroom on haruldane autosomaalse retsessiivse pärandumismustriga haigus, mida põhjustab Wfs1 geeni poolt kodeeritud Wolframiini valgu düsfunktsioon. Wolframi sündroomi esimene sümptom on insuliinist sõltuv diabeet ning sellele järgnevad nägemisnärvi atroofia, magediabeet ja neuroloogilised komplikatsioonid. Insuliinist sõltuv diabeet on kontrollitav insuliini asendusraviga, seega on Wolframi sündroomiga patsientidele enim muret valmistav neurodegeneratsioon, millel puudub ravi. Seepärast on oluline välja töötada neuroprotektiivseid ravimeetodeid, mis oleksid võimelised aeglustama haiguse kulgu ja seeläbi pikendama Wolframi sündroomiga patsientide eluiga.
Wolframiini valgu düsfunktsioonist põhjustatud Wolframi sündroomi uurimiseks on meie uurimisrühm loonud Wfs1 KO roti, kelle Wfs1 geeni viies kodeeriv ekson on deleteeritud. Antud doktoritöö eesmärk oli iseloomustada Wfs1 KO roti fenotüüpi, eesmärgiga kasutada seda uute ravistrateegiate väljatöötamisel. Antud töös pöörati erilist tähelepanu Wolframi sündroomiga seotud neurodegeneratsioonile, mida on insuliinist sõltuva diabeediga võrreldes vähe uuritud.
Käesolevas doktoritöös selgus, et Wfs1 KO rottidel tekkisid Wolframi sündroomi peamised sümptomid: insuliinist sõltuv diabeet ja neurodegeneratsioon. See näitab, et Wfs1 KO rott on tõepoolest Wolframi sündroomi loommudel ja seda saab kasutada Wolframi sündroomi ravistrateegiate testimiseks. Diabeedivastane ravim liraglutiid kaitses Wfs1 KO rotte glükoositalumatuse tekke eest. Lisaks vähendas ravi liraglutiidiga neuropõletikku oliivituumades, ER-stressi ja neuronite ruumala suurenemist (neuronal swelling). Lisaks oli BDNF-i mimeetikul 7,8-dihüdroksüflavoonil (7,8-DHF) põletikuvastastane toime hipokampusele ja säilitas kognitiivse funktsiooni Wfs1 KO loomadel, kuigi 7,8-DHF-il diabeedivastast toimet ei tuvastatud. Seetõttu võib ravi liraglutiidiga, või liraglutiidi ja 7,8-DHF-i koosmanustamine Wolframi sündroomiga patsientidel olla paljutõotavaks ravistrateegiaks. Prekliinilistest uuringutest inspireerituna on alustatud kliinilist uuringut liraglutiidiga, seega selgitavad edasised uuringud välja liraglutiidi toime Wolframi sündroomiga patsientidele.
Wolfram syndrome is a rare hereditary disorder that is caused by biallelic mutations in the WFS1 gene, from which WFS1 (Wolframin) protein is encoded. Wolfram syndrome starts with diabetes mellitus followed by optic nerve atrophy and neurodegeneration. As no effective therapy is available, drug repurposing could be the best therapeutic option because the drugs are already approved and thereby reach patients faster. GLP-1 receptor agonists are used for the treatment of diabetes mellitus and have neuroprotective properties in addition to glucose-lowering effects. Hence, they could also have a potential therapeutic effect for the main symptoms of Wolfram syndrome. In addition to GLP-1 receptor agonists, the neurotrophic factor, such as BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF), has not been studied in connection with Wolfram syndrome. In vivo investigations for drug repurposing would not be possible without well-characterized animal models. Therefore, our research group has created Wfs1 KO rats with an exon 5 disruption. The aim of this dissertation is (i) to evaluate the symptoms of Wolfram syndrome in Wfs1 KO rats and (ii) to use it to test novel treatment strategies for Wolfram syndrome with an emphasis on neurodegeneration. The current thesis demonstrates that Wfs1 KO rats developed the main symptoms of Wolfram syndrome: diabetes mellitus and neurodegeneration. This indicates that the Wfs1 KO rat is indeed a Wolfram syndrome animal model, and it can be used to test treatment strategies for Wolfram syndrome. The anti-diabetic drug liraglutide protected Wfs1 KO rats against development of glucose intolerance. Moreover, liraglutide treatment had a neuroprotective effect in the olive nucleus, as measured by decreased neuroinflammation, ER stress and neuronal swelling. Additionally, BDNF mimetic 7,8-DHF had an anti-inflammatory effect on the hippocampus and maintained cognitive function in Wfs1 KO animals. However, an anti-diabetic effect of 7,8-DHF was not detected. Therefore, liraglutide treatment alone or co-treatment with liraglutide and 7,8-DHF could be promising treatment strategies for Wolfram syndrome patients. Inspired by preclinical studies, a liraglutide clinical trial has been initiated, and further investigations will clarify the effect of liraglutide in Wolfram syndrome patients
Wolfram syndrome is a rare hereditary disorder that is caused by biallelic mutations in the WFS1 gene, from which WFS1 (Wolframin) protein is encoded. Wolfram syndrome starts with diabetes mellitus followed by optic nerve atrophy and neurodegeneration. As no effective therapy is available, drug repurposing could be the best therapeutic option because the drugs are already approved and thereby reach patients faster. GLP-1 receptor agonists are used for the treatment of diabetes mellitus and have neuroprotective properties in addition to glucose-lowering effects. Hence, they could also have a potential therapeutic effect for the main symptoms of Wolfram syndrome. In addition to GLP-1 receptor agonists, the neurotrophic factor, such as BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF), has not been studied in connection with Wolfram syndrome. In vivo investigations for drug repurposing would not be possible without well-characterized animal models. Therefore, our research group has created Wfs1 KO rats with an exon 5 disruption. The aim of this dissertation is (i) to evaluate the symptoms of Wolfram syndrome in Wfs1 KO rats and (ii) to use it to test novel treatment strategies for Wolfram syndrome with an emphasis on neurodegeneration. The current thesis demonstrates that Wfs1 KO rats developed the main symptoms of Wolfram syndrome: diabetes mellitus and neurodegeneration. This indicates that the Wfs1 KO rat is indeed a Wolfram syndrome animal model, and it can be used to test treatment strategies for Wolfram syndrome. The anti-diabetic drug liraglutide protected Wfs1 KO rats against development of glucose intolerance. Moreover, liraglutide treatment had a neuroprotective effect in the olive nucleus, as measured by decreased neuroinflammation, ER stress and neuronal swelling. Additionally, BDNF mimetic 7,8-DHF had an anti-inflammatory effect on the hippocampus and maintained cognitive function in Wfs1 KO animals. However, an anti-diabetic effect of 7,8-DHF was not detected. Therefore, liraglutide treatment alone or co-treatment with liraglutide and 7,8-DHF could be promising treatment strategies for Wolfram syndrome patients. Inspired by preclinical studies, a liraglutide clinical trial has been initiated, and further investigations will clarify the effect of liraglutide in Wolfram syndrome patients
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Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
animal experiments, phenotype, Wolfram syndrome, hypoglycemic drugs, neuroprotective effect