Cerebrovascular Effects Of Voglibose On Ischemic Stroke In Animal Model Of Type 2 Diabetes

Abstract

Aim and Objective: Stroke is a sudden loss of neurologic function resulting from focal disturbance of cerebral blood flow due to ischemia or hemorrhage. Several clinical series of diabetic patients and population-based studies have shown that diabetic patients have about 2-fold higher risk for stroke compared to control subjects. In Type 2 Diabetes Mellitus, the degree of hyperglycemia and long duration of diabetes are risk factors for stroke. Several reports indicate that voglibose has lipid lowering and free radical scavenging effect. The aim of this study is to elucidate whether improving the postprandial state by voglibose leads to the reduction of brain infarct volume and oxidative stress markers in middle cerebral artery occluded (MCAO) stroke prone type 2 diabetic rats. Material and Methods: Healthy Sprague Dawley rats of either sex weighing 150-250 gm were used for the study. They were bred under well-controlled conditions of temperature, humidity and 12h/12h light-dark. The animals were divided in randomized way into ten groups: normal control, normal control + sham operated, normal treated with voglibose (10mg/kg/day, p.o.) + sham operated, normal Control + MCAO operated, normal treated with voglibose (10mg/kg/day, p.o.)+MCAO operated, diabetic control, diabetic control + sham operated, diabetic treated with voglibose (10mg/kg/day, p.o.)+sham operated, diabetic control+ MCAO operated and diabetic treated with voglibose (10mg/kg/day, p.o.)+MCAO operated. Type-2 diabetes was induced in respective groups by single I.V. injection of streptozotocin (STZ) with dose of 90 mg/kg of neonate body weight. The treatment with voglibose (10mg/kg/day, p.o.) started after 6 weeks of diabetes induction and was continued for 8 weeks. After 8 weeks, all the animals were anaesthetized with chloral hydrate (350 mg/kg, i.p.). The middle cerebral artery was occluded with a 4-0 suture coated with poly-l-lysine for 2 h. The suture was removed after 2 h, to allow reperfusion injury. After 72 hours of surgery, blood was collected from retroorbital plexus and the animals were sacrificed. Various parameters like brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, seum glucose, CK-MB, LDH determination, lipid profile, oxidative stress parameters and aldose reductase activity were measured. Results: Normal MCAO animals treated with voglibose showed significant reduction in brain infarct volume, difference in brain hemisphere weight, neurological score, Na+-K+ Diabetic MCAO animals treated with voglibose showed significant reduction in brain infarct volume, difference in brain hemisphere weight, neurological score, Na ATPase activity, serum CK-MB and LDH levels as compared to the normal control animals. No significant changes were observed in the serum glucose levels and lipid profile between the normal control + MCAO and normal control + MCAO + voglibose treated animals. Also, a significant increase in antioxidant parameters like reduced glutathione level, catalase and superoxide dismutase level and significant decrease in malionaldehyde, nitrite level levels and % aldose reductase activity as compared to normal control group. +-K+ Conclusion: ATPase activity, serum CK-MB, LDH, glucose level, cholesterol, triglyceride and LDL levels as compared to the diabetic control group. Also, a significant increase in HDL levels was observed in voglibose treated diabetic MCAO group as compared to diabetic control group. Voglibose treated diabetic MCAO animals also showed significant increase in antioxidant parameters like reduced glutathione level, catalase and superoxide dismutase level and significant decrease in malionaldehyde, nitrite level levels and % aldose reductase activity as compared to diabetic control animals. The study suggests that treatment with voglibose shows protective effect towards cerebrovascular injury by reducing brain infarct volume, weight difference of brain hemisphere, neurological deficit and serum LDH, Na+-K+ ATPase and CK-MB activity in normal as well as diabetic animals. In the postprandial state, generation of oxidative stress occurs followed by increase in Na+-K+ ATPase activity, activation of cerebrovascular events and neurological dysfunction. The possible mechanism of action of voglibose can be reduction in oxidative stress by decreasing glucose toxicity in postprandial state.