Mechanisms of Sulfonylureas-induced neuroprotection – NEUROGLI

In a previous ANR project, we showed that glibenclamide, a sulfonylurea which binds SUR1 and SUR2 receptors, even at non-hypoglycemic doses, protects the retina from neuronal destruction in models of hyperglycemia and excitotoxicity. We have shown that this effect is dependent on the SUR1 protein which is extensively expressed in rodent, monkey and human retinas. We have identified the molecules most regulated by glibenclamide during this process of neuroprotection. A recent preliminary experiment in rats invalidated for lipocalin 2 points to this molecule as an important target involved in neuroprotection. In the current NEUROGLI project, we will validate our preclinical results in patient cohorts; we will validate that neuroprotective effect is a drug class effect dependent on SUR1; we will characterize the ion channels associated with SUR1 during retinal neuroprotection. We will validate target effectors: as a priority, lipocalin 2, in our models of diabetic retinopathy, in rats and mice invalidated for the genes studied, as well as in patient biological samples. Our goal is to provide a strong rationale for repositioning these sulfonylureas as neuroprotectors. This is important and innovative because the new data concerning diabetic retinopathy show that its incidence continues to increase despite therapeutic progress and show that neuronal loss precedes the signs of microangiopathy conventionally sought in patients. Knowledge of the neuroprotective properties of these well-known and low-cost molecules opens up possibilities for use by local ocular or systemic route, including in developing countries.