title: In vivoEvaluation of Two Thiazolidin-4-one Derivatives in High Sucrose Diet Fed Pre-diabetic Mice and Their Modulatory Effect on AMPK, Akt and p38 MAP Kinase in L6 Cells.
abstract: We had previously demonstrated the anti-diabetic potential and pancreatic protection of two thiazolidin-4-one derivatives containing nicotinamide moiety (NAT-1 and NAT-2) in STZ-induced diabetic mice. However, due to the limitations of the STZ model, we decided to undertake a detailed evaluation of anti-diabetic potential of the molecules on a high sucrose diet (HSD) fed diabetic mouse model. Further,in vitromechanistic studies on the phosphorylation of AMPK, Akt and p38 MAP kinase in L6 myotubes and anti-inflammatory studies in RAW264.7 mouse monocyte macrophage cells were performed. 15 months of HSD induced fasting hyperglycaemia and impaired glucose tolerance in mice. Treatment with NAT-1 and NAT-2 (100 mg/kg) for 45 days significantly improved the glucose tolerance and lowered fasting blood glucose levels compared to untreated control. An improvement in the elevated triglycerides and total cholesterol levels, and favorable rise in HDL cholesterol were also observed with test drug treatment. Also, no major changes were observed in the liver (albumin, AST and ALT) and kidney (creatinine and urea) parameters. This was further confirmed in their respective histology profiles which revealed no gross morphological changes. In L6 cells, significant phosphorylation of Akt and p38 MAP kinase proteins were observed with 100 μM of NAT-1 and NAT-2 with no significant changes in phosphorylation of AMPK. The molecules failed to exhibit anti-inflammatory activity as observed by their effect on the generation of ROS and nitrite, and nuclear levels of NF-κB in LPS-stimulated RAW264.7 cells. In summary, the molecules activated Akt and p38 MAP kinase which could have partly contributed to their anti-hyperglycaemic and hypolipidemic activitiesin vivo.
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Jayesh
authors: J
authors: Mudgal
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Priya
authors: P
authors: Shetty
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Neetinkumar D
authors: ND
authors: Reddy
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal UniversityManipal, India; Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal UniversityManipal, India.
authors: H S
authors: HS
authors: Akhila
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Karthik
authors: K
authors: Gourishetti
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Geetha
authors: G
authors: Mathew
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Pawan G
authors: PG
authors: Nayak
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Nitesh
authors: N
authors: Kumar
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Anoop
authors: A
authors: Kishore
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Nampurath G
authors: NG
authors: Kutty
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Krishnadas
authors: K
authors: Nandakumar
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Rekha R
authors: RR
authors: Shenoy
authors: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Chamallamudi M
authors: CM
authors: Rao
authors: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University Manipal, India.
authors: Alex
authors: A
authors: Joseph
keywords: AMPK; Akt; high sucrose diet; mouse model; p38 MAP kinase; thiazolidin-4-one derivatives