Evaluation of role of Magnesium Valproate on type 2 diabetes induced cardio-renal complications

Abstract

Background and Objective- Cardiomyopathy and Nephropathy is the leading cause of morbidity and mortality in patients associated with type 2 diabetes. Histone hyperacetylation is known to exhibit cardioprotective and renoprotective role. Valproic acid has been shown to inhibit histone deacetylase thus causing hyperacetylation of histone proteins We have studied the effect of 8 weeks treatment with MgV on cardiovascular and renal complications associated with streptozotocin (STZ) induced diabetes in neonatal rats. Material and methods - Sprague Dawley rats of 2 day age were made diabetic with STZ (90 mg kg-1, ip). Various biochemical, cardiac, hemodynamic and urine parameters were measured at the end of 8 weeks of treatment with MgV. Results- STZ treated diabetic rats showed increase in food and water intake and decrease in body weight. Treatment with MgV produced significant decrease in food and water intake and significantly increased the body weight. STZ produced significant hyperglycaemia and dyslipidaemia which includes increased serum level of glucose ,LDL, total cholersterol ,VLDL ,triglyceride and significantly decreased HDL level and logTG/HDL ratio. Treatment with MgV significantly decreased hyperglycaemia, total cholesterol, LDL, VLDL and triglyceride levels while produced significant increase in HDL level and logTG/HDLratio.There was significant increase in the cardiac biomarker level in STZ treated diabetic rat which includes increased level of LDH,CK-MB and CRP.Chronic treatment with MgV exhibited significant reduction in cardiac biomarker level.STZ treated rats was associated with haemodynamic change accompanying hypertension, bradycardia, reduced rate of pressure development and decay. MgV improved haemodynamic function by controlling hypertension and bradycardia and significantly increase the rate of pressure development and decay. Diabetic rats also showed significantly increased cardiac hypertrophy index(CHI), left ventricular(LV) hypertrophy index, LV/RV ratio, LV collagen deposition and LV cardiomyocyte diameter . Chronic treatment with MgV significantly reduced CHI, LV hypertrophy index, LV/RV ratio, LV collagen deposition and LV cardiomyocyte size.STZ treated rat showed imbalance between pro-oxidant and antioxidant compounds and exhibited increased LV prooxidant levels like nitrite and malondialdehyde and significantly reduced LV antioxidant enzyme activity like superoxide dismutase(SOD) and reduced glutathione(GSH) level . STZ also significant reduced LV Na+/K+ ATPase enzyme activity. Chronic treatment with MgV significantly decreased LV nitrite and malondialdehyde levels while significantly increased SOD activity, GSH levels as well as Na+/K+ ATPase enzyme activity.Histological studies revealed that the diabetic rats exhibited fibrosis,distortion,clustering of nuclei etc .Treatment with MgV significantly regress the pathological alteration of LV. STZ treated rats showed significantly high serum levels of alkaline phosphatase(ALP), creatinine, uric acid, blood urea nitrogen(BUN), BUN:Creatinine ratio and significantly low level of serum albumin. Treatment with MgV significantly decreased serum levels of ALP, creatinine, uric acid, BUN, BUN:Creatinine ratio and significantly increased serum albumin level. Furthermore, diabetic rats showed significantly reduced uric acid, creatinine and urinary sodium and chloride excretion and creatinine clearance and significantly increased urinary albumin, urinary albumin:creatinine ratio and total protein levels. Treatment with MgV significantly increased uric acid, creatinine and urinary electrolytes excretion and creatinine clearance and significantly decreased urinary albumin, urinary albumin:creatinine ratio and total protein levels. STZ treated rat showed increased LV prooxidant levels like nitrite and malondialdehyde and significantly reduced LV antioxidant enzyme activity like superoxide dismutase(SOD) and reduced glutathione(GSH) level. Diabetic rats also showed significantly increased renal tissue collagen deposition and treatment with MgV significantly reduced renal tissue collagen deposition. Histological analysis showed increased glomerular lesions, mesangial expansion and tubular atrophy. Chronic treatment with MgV produced regression in pathological alterations of kidney. Magnesium valproate showed no CNS side effect in diabetic treated rats which was evident from locomotor activity and forced swimming test. Conclusions- Our data suggests that MgV has beneficial effect on cardiovascular complications associated with streptozotocin (STZ) induced diabetes in neonatal rats as depicted by prevention of hyperglycemia, hyperinsulinaemia, dyslipidemia, hypertension, bradycardia, cardiac and left ventricular hypertrophy, oxidative stress, reduction in cardiac biomarker levels and preserving structural integrity of the myocardium. In addition, it also prevents renal complications by controlling urinary electrolytes, preserving kidney function decreasing microalbuminuria and regressing pathological alteration of kidney.Thus MgV could be considered as an “add on” therapy for management of cardio-renal complication of diabetes.