Pharmacological Evaluation of Novel Tyrosine Kinase Inhibitor in Combination with PPAR-Y Against for Treatment of Metabolic Dysfunction

Abstract

Aim and objective: Many study reports showed that tyrosine kinase inhibitors reverse type 2 diabetes in CML patients. Thiazolidenediones which are hypoglycemic agents exhibit mark improvement in glycemic control and insulin sensitivity in type 2 diabetes. Molecular docking studies suggest that tyrosine kinase inhibitors bind with PPAR-γ in ligand binding domain with high predictive values. These investigations suggested us further evaluation of tyrosine kinase inhibitor in combination with PPAR-γ agonist in in vivo animal models. Therefore, present study focuses on pharmacological evaluation of synthetic Tyrosine kinase inhibitor in combination with PPAR𝛾 agonist for treatment of type 2 diabetes. Material and method: For this study we used six to ten weeks old male and female wistar rats. Induction was done with 20 % w/v fructose solution for 8 weeks. TKI was synthesized and administered at dose 2.5mg/kg, Dasatinib was also administered at dose 2.5 mg/kg. Pioglitazone was administered at dose 25mg/kg for 7 days. At the end of treatment, effect on glucose homeostasis was measured by oral glucose tolerance test. The blood glucose levels and body weight were monitored before and after treatment. Lipid profile was also measured with different test. Liver inflammation and lipid infiltration in adipocytes were assessed by histopathology using H & E staining. Results: Combination therapy produced statistically significant improvement in blood glucose levels after 7 days of treatment as compared to monotherapy. TKI+PIO group also showed improvement in weight gain after treatment period. Lipid infiltration and inflammation of liver cells were decreased by both combination therapies which was shown by decreased adipocytes size and hypertrophy of liver cells. Conclusion: The present study gives in vivo evidences that test TKI drug and PPAR-γ agonist combination significantly attenuated glucose intolerance. The combination also showed synergistic effect by improvement in elevated blood glucose levels. Thus, combination therapy may improve sustained glycaemic control by preserving pancreatic function. Therefore, TKI and PPAR-γ agonist combination therapy could be beneficial treatment option for type 2 diabetes.