Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

Abstract

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.

Antioxidant Effects of DPP-4 Inhibitors in Early Stages of Experimental Diabetic Retinopathy

“…In the present study, we demonstrated the antioxidant and the anti-inflammatory properties of sitagliptin, a DPP-4i, in an experimental model of DR. These findings support and reinforce previous evidence showing the beneficial effects of topical administration of sitagliptin in early stages of DR [ 12 , 13 ].…”

“…Therefore, the search for new treatments targeting the earliest and asymptomatic stages of DR at the onset of NVU impairment is an unmet medical need that has to be urgently addressed [ 11 ]. In this context, a new therapeutic strategy is the topical administration (eye drops) of dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4i), which have demonstrated promising results in experimental models of DR [ 12 , 13 ]. Through the nondegradation of glucagon-like peptide-1 (GLP-1), the main target of the DPP-4 enzyme, and through other independent and not clearly elucidated mechanisms, DPP-4i significantly prevents the appearance of the main hallmarks of DR, glial activation, and neuronal cell death, as well as preserving the functionality of the retina [ 12 , 13 , 14 ].…”

“…In this context, a new therapeutic strategy is the topical administration (eye drops) of dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4i), which have demonstrated promising results in experimental models of DR [ 12 , 13 ]. Through the nondegradation of glucagon-like peptide-1 (GLP-1), the main target of the DPP-4 enzyme, and through other independent and not clearly elucidated mechanisms, DPP-4i significantly prevents the appearance of the main hallmarks of DR, glial activation, and neuronal cell death, as well as preserving the functionality of the retina [ 12 , 13 , 14 ]. In the present study, we explored the potential antioxidant effects of topical administration of DPP-4i in an experimental model of DR.…”

Transcriptomic Analysis Reveals That Retinal Neuromodulation Is a Relevant Mechanism in the Neuroprotective Effect of Sitagliptin in an Experimental Model of Diabetic Retinopathy

“…In both studies, sitagliptin was administered orally, and the effects can be attributed to the systemic improvement due to the lowering of blood glucose levels. Nevertheless, our group demonstrated that sitagliptin eye drops are able, in a non-glycaemia-dependent fashion, to significantly prevent the diabetes-induced synaptic failure that occurred in the retina of db/db mice, evidencing the intrinsic neuroprotective properties of DPP-4i [15]. Considering these previous studies, the GSEA results obtained reveal that, among the different beneficial effects of DPP-4i in DR models, retinal neuroprotection is the most relevant one.…”

Continuous Glucose Monitoring as an Additional Tool in Early Cystic Fibrosis-Related Diabetes Monitoring and in Evaluation of Short-Term Sitagliptin Response

“…In addition, sitagliptin has beneficial effects on diseases derived from complications of diabetes mellitus, such as ischaemic heart disease [ 34 ], atherosclerosis, and hypertension [ 35 ]. Sitagliptin also appears to be useful in the initial treatment of microangiopathic complications of diabetes, such as diabetic retinopathy [ 36 , 37 , 38 ] and diabetic nephropathy [ 39 ], in experimental models. In addition, sitagliptin appears to have pleiotropic effects, including effects on COVID-19 infection.…”