Neuroprotective effects of glucose-lowering drugs in rat focal brain ischemia-reperfusion model

Background. Ischemic stroke is one of the leading causes of death in patients with type 2 diabetes mellitus (DM). According to the results of clinical and experimental studies, the ability of glucagon-like peptide-1 receptor agonists (GLP-1RA) to reduce the risk and severity of stroke in DM has been proven; data on the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) effect are scarce. There has been no direct comparative study of the GLP-1RA and SGLT-2i neuroprotective effect.

Objective. To evaluate and to compare the effect of GLP-1RA of varying duration of action and SGLT-2i of varying selectivity on the neurological deficit severity and the brain damage volume in a transient focal brain ischemia model in rats without DM.

Design and methods. Male Wistar rats were divided into groups (n = 10 each) depending on the therapy received: “EMPA” (empagliflozin per os 2 mg/kg once daily), “CANA” (canagliflozin per os 25 mg/kg once daily), “LIRA” (liraglutide 1 mg/kg s. c. once daily), “DULA” (dulaglutide 0,12 mg/kg s. c. every 72 hours), “SEMA” (semaglutide 0,012 mg /kg s. c. once daily), “MET” (metformin per os 200 mg/kg once daily — comparison group), “Control” (administration of 0,9 % NaCl solution s. c. once daily). After 7 days, all groups underwent transient focal 30-minute filament middle cerebral artery occlusion. After 48 hours of reperfusion, neurological deficit was assessed using the Garcia scale, then the brain was collected and sections were stained with 1 % triphenyltetrazolium chloride solution to calculate the damage volume.

Results. Neurological deficit severity in the “LIRA” (14,50 (12,25; 15,25) points) and “SEMA” (14,00 (13,50; 18,00) points) groups was significantly less than in the “Control” group (11.00 (6,75; 12,00) points). The use of both SGLT-2i, as well as metformin, had no effect on the neurological status. At the same time, therapy with all study drugs had an infarct-limiting effect, compared with the “Control” group (damage volume 24,50 (14,69; 30,12) % of the total brain volume). At the same time, the brain damage volume in the “MET” group (12,93 (6,65, 26,66) %) was greater than that in the “EMPA” (6,08 (2,97, 7,63) %), “CANA” (5,11 (3,96; 8,34) %), “LIRA” (3,40 (2,09; 8,08) %), “DULA” (4,37 (2,72; 5,40) %), “SEMA” (5,19 (4,11; 7,83) %) groups.

Conclusions. SGLT-2i of varying selectivity and GLP-1RA of varying duration of action have a similar infarct-limiting effect in acute experimental brain ischemia. At the same time, GLP-1RA neuroprotective potential is higher, as it is characterized by an additional positive effect on the neurological status.

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