Neurological disorders in animals with cerebral ischemia and diabetes mellitus and their correction by a new agonist gpr119 and its combinations with metformin and citicoline

Type 2 diabetes mellitus (DM2) significantly increases the risk of stroke, and the choice of hypoglycemic therapy may influence not only a probability of stroke but also severity of cerebrovascular disease. Objective: To evaluate the effect of combination treatment with a GPR119 agonist, metformin and citicoline on severity of neurological disorders in animals with stroke and diabetes. Cerebral ischemia was modeled by intraluminal occlusion of the middle cerebral artery (OMCA). Methods. The study was performed on Wistar rats with 28-day streptozotocin-nicotinamide-induced diabetes. The GPR119 receptor agonist (dipiaron) and its combination with metformin were administered starting from the first day of DM, and citicoline was administered after the induction of brain ischemia. Behavioral and neurological disorders were evaluated using the Combs & D’Alecy and Garcia scales, and the open field, Rotarod, and active and passive avoidance tests. Results. The metformin treatment normalized glycemia but did not alleviate severity of the neurological deficit induced by subsequent OMCA. The groups treated with dipiaron and its combination with metformin, in addition to improved glycemic control, showed significant decreases in brain infarction volume and edema and the severity of neurological disorders in surviving animals compared to the control (p<0.05). Administration of citicoline without the hypoglycemic therapy reduced the neurological deficit in comparison with the control group. Addition of citicoline to the hypoglycemic therapy did not significantly reduce the severity of brain ischemia. Conclusion. The combination treatment of animals with brain ischemia and diabetes with the GPR119 agonist and metformin significantly enhanced the therapeutic potential of both drugs evident as a better glycemic control and alleviated severity of the neurological deficit following OMCA.