Beneficial effects of co-administration of PPAR-γ agonist with melatonin on cardiovascular complications associated with diabetes

Abstract

Aim: Effect of PPAR-g agonists, Thiazolidinediones, in combination with melatonin was studied for cardiovascular complications associated with diabetes. Materials and Methods: Diabetic rats were treated with combination of pioglitazone (10 mg/kg/day p.o.) or rosiglitazone (5 mg/kg/day p.o.) with melatonin (10 mg/kg/day p.o.) for 7 weeks. The biochemical parameters, serum glucose, triglyceride, total cholesterol, HDL-cholesterol, AST, LDH and LDL-cholesterol levels were evaluated at the end of 7 weeks. Also cardiovascular parameters like atherogenic index, blood pressure, hisotology of heart were done. Results and Conclusions: The combination treated groups, pioglitazone plus melatonin (PM) and rosiglitazone plus melatonin (RM), showed significant decrease in the blood pressure when compared with diabetic control group. The level of cell injury markers AST and LDH was normalized in the combination groups PM and RM along with significant decrease in the atherogenic index. In the biochemical parameters, the serum glucose, triglyceride, total cholesterol, HDL-cholesterol, and LDL-cholesterol levels were significantly lowered in the combination groups. There was significant inhibition of the myonecrosis, reduction in the infiltration and inflammatory cells, and vacuolar changes when compared with diabetic control. The combination treated groups also proved to be effective in normalizing the levels of SOD, GSH, catalase, and LPO in heart homogenates when compared with diabetic control as well as pioglitazone, rosiglitazone, and melatonin-alone-treated groups. Hence, it may be concluded that the combination of PPAR-g agonists, thiazolidinediones, with melatonin may be beneficial in the treatment of diabetes-induced cardiovascular complications.

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Diabetic cardiomyopathy is characterized by increased myocardial fibrosis and stiffness, with this being associated with the impaired diastolic function, late systolic dysfunction resulting in the inability of the heart to pump enough blood through the body, a state called heart failure [72]. The main pathogenetic factors involved in the development and progression of diabetic cardiomyopathy include hyperglycemia, systemic insulin resistance, and impaired cardiac insulin metabolic signaling; these factors induce several pathways including vascular endothelial dysfunction, adrenergic activity, impairment of mitochondria calcium (Ca 2+ ) handling, activation of renin-angiotensin system, myocardial ischemia/functional hypoxia, oxidative stress, mitochondria dysfunction, inflammation, endoplasmic reticulum stress and cardiomyocyte death [72,73]. Excessive level of reactive oxygen species (ROS) induced by high glucose contributes to the peroxidation of lipids, induction of apoptosis and inhibition of autophagy in muscle fibers [74]; diabetes impairs myocardial mitochondrial biogenesis and suppresses the activity of myocardial mitochondrial Complexes I, III and IV resulting in the loss of mitochondrial number, impairment of mitochondrial function, increased generation of ROS and escape of death-inducing factors [75].…”

“…Co-administration of PPAR-g agonist, thiazolidinediones, with melatonin has been reported to have beneficial effects on diabetesinduced cardiovascular complications. Combination of pioglitazone or rosiglitazone with melatonin is effective to normalize levels of SOD, glutathione (GSH), CAT, and lipid peroxidation as well as inhibit myonecrosis, vacuolar changes and infiltration of inflammatory cells in the heart tissue of alloxan-induced diabetic rats; this indicates that melatonin may be a potential drug to increase beneficial effect of thiazolidinediones on diabetic cardiomyopathy [73]. Melatonin treatment may also prevent the development of diabetic cardiomyopathy through increasing the phosphorylation of vascular endothelial growth factor-A (VEGF-A) resulting in the inhibition of cardiac enlargement and hypertrophy in STZ-induced diabetic rats [85].…”

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: Effect of Mesenchymal Stem Cell with PPAR-γ Agonist or Exendin-4

“…Group 4 (D + PPAR): the diabetic rats were administered pioglitazone; a PPAR-γ agonist, (10 mg/kg/day) by oral gavage [20] for the next 4 weeks.…”

“…Group 5 (D + PPAR + MSC): the diabetic rats received single i.v. of MSCs (1 × 10 6 cells/ml) [19] and pioglitazone (10 mg/kg/day, orally [20]) daily, for 4 weeks.…”