Dose-related antihyperglycemic and hypolipidemic effects of two novel thiazolidin-4-ones in a rodent model of metabolic syndrome

Sebastian, Sarine and Gowdra, Vasantharaju S and Kishore, Anoop and Mudgal, Jayesh and Nandakumar, Krishnadas and Thambi, Magith and Mathew, Geetha and Nampurath, Gopalan Kutty (2015) Dose-related antihyperglycemic and hypolipidemic effects of two novel thiazolidin-4-ones in a rodent model of metabolic syndrome. Journal of Diabetes, 2015. pp. 1-11. ISSN 1753-0407

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Abstract

BACKGROUND:The replacement of the thiazolidinedione moiety with a thiazolidinone may yield antidiabetic compounds with similar pleiotropic effects. Hence, the aim of the present study was to explore the dose-related antihyperglycemic and hypolipidemic effects of two synthesized novel thiazolidin-4-one derivatives, one with a nicotinamide and the other with a p-chlorophenoxyacetamide substitution at the N3 position of the thiazolidinone ring (NAT1 and PAT1, respectively), in a rodent model of metabolic syndrome (MetS). METHODS:Metabolic syndrome was induced in Wistar rats by neonatal administration of monosodium glutamate (i.p.) on 4 consecutive days followed by high-sucrose diet feeding for 6 months. The effects of NAT1 (33 and 66 mg/kg) and molar equivalent doses of PAT1 (40 and 80 mg/kg) on relevant biochemical parameters were evaluated. Because MetS is a state of chronic low-grade inflammation, we also evaluated the effects of these compounds on proinflammatory markers, namely interleukin (IL)-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), and nitric oxide (NO). RESULTS:Both NAT1 and PAT1 attenuated hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, and glucose intolerance. PAT1 exhibited superior antihyperglycemic and antihypoalphalipoproteinemic effects than NAT1. However, NAT1 had a better triglyceride-lowering effect. At the lower dose tested, both compounds significantly reduced elevated malondialdehyde levels. In addition, PAT1 (80 mg/kg) restored hepatic superoxide dismutase enzyme levels. There was a tendency for NAT1 and PAT1 to inhibit elevated hepatic IL-6 and TNF-α levels, but the differences did not reach statistical significance. In addition, PAT1 exhibited in vitro anti-inflammatory activity by reducing proinflammatory ROS and NO levels in RAW264.7 macrophages. CONCLUSIONS:The novel thiazolidin-4-ones NAT1 and PAT1 could be potential pleiotropic drug candidates targeting MetS.

Item Type: Article
Uncontrolled Keywords: Anti-inflammatory; antihyperglycemic; hypolipidemic; metabolic syndrome; thiazolidin-4-one.
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Quality Assurance
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 14 Jul 2016 10:05
Last Modified: 14 Jul 2016 10:05
URI: http://eprints.manipal.edu/id/eprint/146584

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