Minimum Effective Dose of DPP-4 Inhibitors for Treating Early Stages of Diabetic Retinopathy in an Experimental Model

Abstract

Dipeptidyl peptidase-4 inhibitors; Experimental diabetes; Retinal neurodegeneration

Inhibidores de la dipeptidil peptidasa-4; Diabetes experimental; Neurodegeneración retiniana

Inhibidors de la dipeptidil peptidasa-4; Diabetis experimental; Neurodegeneració de la retina

The neurovascular unit (NVU) plays an essential role in the development of diabetic retinopathy (DR). We previously reported that the topical administration (eye drops) of sitagliptin and saxagliptin, two dipeptidyl peptidase-4 inhibitors (DPP-4i), prevents retinal neurodegeneration and vascular leakage in db/db mice. The aim of the present study is to evaluate the minimum effective dose of the topical administration of these DPP-4i. For this purpose, sitagliptin and saxagliptin were tested at different concentrations (sitagliptin: 1 mg/mL, 5 and 10 mg/mL, twice per day; saxagliptin: 1 and 10 mg/mL, once or twice per day) in db/db mice. As end points of efficacy, the hallmarks of NVU impairment were evaluated: reactive gliosis, neural apoptosis, and vascular leakage. These parameters were assessed by immunohistochemistry, cell counting, and the Evans blue method, respectively. Our results demonstrated that the minimum effective dose is 5 mg/mL twice per day for sitagliptin, and 10 mg/mL twice per day for saxagliptin. In conclusion, this study provides useful results for the design of future preclinical regulatory studies and for planning clinical trials.

This research was funded by grants from the Ministerio de Economía y Competitividad (PID2019-104225RB-I00) and the Instituto de Salud Carlos III (DTS18/0163, PI19/01215 and ICI20/00129). The study funder was not involved in the design of the study.