Neuromodulation Induced by Sitagliptin : A New Strategy for Treating Diabetic Retinopathy
Ramos, Hugo (Vall d'Hebron Institut de Recerca (VHIR))
Bogdanov, Patricia (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Sabater, David (Vall d'Hebron Institut de Recerca (VHIR))
Huerta, Jordi (Vall d'Hebron Institut de Recerca (VHIR))
Valeri, Marta (Vall d'Hebron Institut de Recerca (VHIR))
Hernández, Cristina (Vall d'Hebron Institut de Recerca (VHIR))
Simó Canonge, Rafael (Vall d'Hebron Institut de Recerca (VHIR))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.
Ajuts:	Agencia Estatal de Investigación PID2019-104225RB-I00 Instituto de Salud Carlos III PI19/01215 Instituto de Salud Carlos III ICI20/00129
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Db/db mouse model ; Diabetic retinopathy ; Dipeptidyl peptidase 4 inhibitors ; Presynaptic proteins ; Retinal neurodegeneration ; Sitagliptin
Publicat a:	Biomedicines, Vol. 9 (november 2021) , ISSN 2227-9059

DOI: 10.3390/biomedicines9121772
PMID: 34944588

16 p, 4.8 MB

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