Efeitos anti-inflamatórios não canónicos da sitagliptina, um fármaco oral para a diabetes tipo 2, na microglia: potencial de reposicionamento do fármaco para doenças degenerativas da retina e cérebro

Retinal and brain degenerative diseases affect more than 500 million people worldwide. The treatments available are scarce and not very effective. Therefore, finding novel treatments, particularly for the (very) early stages of the diseases, is an unmet need. These treatments could, at least, delay the disease progression, which would be a significant gain for patients, relatives, health system, society and economy. Sitagliptin was the first gliptin approved (2006 in USA; 2007 in Europe) for the treatment of type-2 diabetes. Since then, more than 10 gliptins were approved. The mechanism of action resides in the inhibition of dipeptidyl peptidase IV (DPP-IV), thus increasing the incretin levels, and consequently the insulin secretion and normalization of glycemic levels. Increasing evidence, mainly using animal models of disease, has shown that sitagliptin and other gliptins have beneficial pleiotropic effects in several organs, including the retina and brain. These effects can be independent of glycemic control, and the molecular and cellular mechanisms have not been clarified yet. The PI Group was the first demonstrating beneficial effects of sitagliptin in the retina of diabetic animal models, decreasing neuroinflammation and cell death. In the brain, there are more studies showing the beneficial effects of gliptins. These findings set the ground for drug repurposing of gliptins. However, it is very important to clarify the mechanisms underlying their beneficial effects. The PI Group has many publications showing that neuroinflammation mediated by microglia, immune cells of the Central Nervous System, has a key role in retinal degeneration, occurring the same in the brain. Therefore, microglia has been considered an interesting therapeutic target. The PI Group has also extensive research showing that adenosine and adenosine receptors, particularly A2A and A3 receptors, can govern microglia reactivity. Also important, are the PI preliminary data showing non-canonical anti-inflammatory effects of sitagliptin exerted directly in microglia, that deserves to be explored (see Annex). Taking these evidences into account, our main goals are: 1. To dissect, at a molecular and cellular level, the non-canonical anti-inflammatory effects of sitagliptin on microglia; 2. To assess, whether the anti-inflammatory effects of sitagliptin detected in BV-2 microglia cell line, also occur and are similar in primary microglia from mouse retina, as well as in microglia derived from human iPSCs; 3. To assess, whether hiPSCs-derived microglia from non-diabetic controls and from patients with proliferative diabetic retinopathy, are differentially affected by sitagliptin and by a pro-inflammatory condition. 4. To dissect the impact of sitagliptin on the adenosinergic system in microglia, including the levels of adenosine and other purines, the expression and activity of several enzymes and transporters, and the expression of A1, A2A and A3 adenosine receptors. 5. To clarify if the non-canonical anti-inflammatory effects of microglia are mediated by adenosine receptors. Altogether, the findings of this project might further support drug repurposing of gliptins for retinal and brain degenerative diseases, opening also doors to carry out well-designed clinical trials, to confirm the beneficial effects of gliptins in these diseases.