In vivo Evaluation 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

Mudgal, Jayesh and Shetty, Priya and Reddy, Neetinkumar D and Akhila, HS and Gourishetti, Karthik and Mathew, Geetha and Nayak, Pawan G and Kumar, Nitesh and Kishore, Anoop and Kutty, Gopalan N and Nandakumar, Krishnadas and Shenoy, Rekha R and Rao, Mallikarjuna C and Joseph, Alex (2016) In vivo Evaluation 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. Frontiers in Pharmacology, 7 (381). pp. 1-10. ISSN 1663-9812

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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 vitro mechanistic studies on the phosphorylation of AMPK, Akt and p38 MAP kinase in L6 myotubes and antiinflammatory 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 mM 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-kB 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 activities in vivo.

Item Type: Article
Uncontrolled Keywords: Thiazolidin-4-one derivatives; High sucrose diet; Mouse model; AMPK; Akt; p38 MAP kinase
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Pharmacy > MCOPS Manipal > Pharmacy Practice
Depositing User: KMC Library
Date Deposited: 22 Oct 2016 08:45
Last Modified: 22 Oct 2016 08:45
URI: http://eprints.manipal.edu/id/eprint/147353

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