Dose-related antihyperglycemic and hypolipidemic effects of two novel thiazolidin-4-ones in a rodent model of metabolic syndrome.
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.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Sarine Sebastian
SS
Karot
Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Vasantharaju Gowdra
VG
Surenahalli
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Anoop
A
Kishore
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Jayesh
J
Mudgal
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Krishnadas
K
Nandakumar
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Magith Thambi
MT
Chirayil
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Geetha
G
Mathew
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India.
Gopalan Kutty
GK
Nampurath
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012970:Sodium Glutamate; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001786:Blood Glucose; D019422:Dietary Sucrose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002784:Cholesterol; D012970:Sodium Glutamate
anti-inflammatory; antihyperglycemic; hypolipidemic; metabolic syndrome; thiazolidin-4-one; 代谢综合征; 噻唑烷-4-酮。; 抗炎; 降血糖; 降血脂