eugenosedin-a and Hyperglycemia

This study examined the effects of eugenosedin-A (Eu-A) in a streptozotocin (STZ)/nicotinamide-induced rat model of type II diabetes mellitus (T2DM). Six-week-old Sprague-Dawley rats were randomly divided into three groups: (1) RD group, normal rats fed a regular diet (RD), (2) DM group, T2DM rats fed a high-fat diet, and (3) Eu-A group, T2DM rats fed a high fat diet plus oral Eu-A (5 mg/kg/day). After 30 days, the DM group had higher body weight, higher blood glucose and lower insulin levels than the RD group. The DM group also had increased protein expression of glycogen synthase kinase (GSK) in liver and skeletal muscle and decreased protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), IRS-2, AMP-activated protein kinase (AMPK), glucose transporter-4 (GLUT-4), glucokinase (GCK), and peroxisome proliferator-activated receptor γ (PPAR-γ). STZ/nicotinamide-induced T2DM increased the expression of mitogen-activated protein kinases (MAPKs: p38, ERK, JNK) and inflammatory p65 protein. In the Eu-A treated T2DM rats, however, blood glucose was attenuated and the insulin concentration stimulated. Changes in IR, IRS-1 and IRS-2 proteins as well as AMPK, GLUT-4, GCK, GSK, PPAR-γ, MAPKs, and inflammatory p65 proteins were ameliorated. These results suggested that Eu-A alleviates STZ/nicotinamide-induced hyperglycemia by improving insulin levels and glucose metabolism, and inhibiting the MAPKs- and p65-mediated inflammatory pathway.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Gene Expression Regulation; Glucokinase; Glucose Transporter Type 4; Glycogen Synthase Kinases; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Liver; Male; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Niacinamide; Piperazines; PPAR gamma; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Signal Transduction; Streptozocin; Transcription Factor RelA

Eugenosedin-A is a serotonin (5-hydroxytryptamine; 5-HT) 5-HT(1B/2A) and alpha(1)/alpha(2)/beta(1)-adrenoceptor blocker with anti-oxidative, anti-inflammatory and free-radical scavenging activities. Previous reports demonstrated that 5-HT(2A) blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin-A and other agents in treating hyperlipidaemia.. C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high-fat diet alone or supplemented with one of five agents: eugenosedin-A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks.. Compared with the regular diet, the mice fed the high-fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin-A to the high-fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol-CoA desaturase) and restored adipose peroxisome proliferator-activated receptor gamma expression. Eugenosedin-A also enhanced low-density lipoprotein receptor mRNA expression.. Eugenosedin-A may improve plasma lipid metabolism by increasing low-density lipoprotein receptor and peroxisome proliferator-activated receptor gamma expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol-CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity-related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin-A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti-peroxidation effects in mice fed a high-fat diet.

Topics: Adipose Tissue; Animals; Atorvastatin; Blood Glucose; Body Weight; Brain; Dietary Fats; Female; Glutathione Peroxidase; Heptanoic Acids; Hyperglycemia; Hyperlipidemias; Insulin; Ketanserin; Lipid Peroxidation; Lipogenesis; Liver; Malondialdehyde; Mice; Mice, Inbred C57BL; Piperazines; PPAR gamma; Prazosin; Propranolol; Pyrroles; Superoxide Dismutase; Weight Gain

Eugenosedin-A has been demonstrated to possess alpha/beta-adrenoceptor and serotonergic receptor blocking activities. We have investigated by what mechanisms eugenosedin-A prevents lipopolysaccharide (LPS)-induced hypotension, vascular hyporeactivity, hyperglycaemia, oxidative injury or inflammatory cytokines formation in rats. Intravenous administration of eugenosedin-A, trazodone, yohimbine (1 mg kg(-1)), aminoguanidine or ascorbic acid (15 mg kg(-1)) normalized LPS (10 mg kg(-1))-induced hypotension. Pretreatment with eugenosedin-A or the other agents 30 min before LPS injection reduced aortic hyporeactivity. LPS-induced increases in plasma interleukin-1beta (IL-beta), IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and blood glucose levels were significantly inhibited by eugenosedin-A (1 mg kg(-1), i. v.). The same dose of trazodone, a chloropiperazinylbenzene-type antidepressant, and yohimbine, an alpha(2)-adrenoceptor antagonist, reduced IL-1beta and TNF-alpha, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased IL-1beta, TNF-alpha contents and hyperglycaemia. Eugenosedin-A and the other agents inhibited Fe(2+)-ascorbic acid-induced peroxidation in rat cortex, indicating that those agents had antioxidant effects, with the exception of aminoguanidine. In free radical scavenged experiments, eugenosedin-A and ascorbic acid eliminated peroxyl radicals. All test agents inhibited the LPS-induced increase of malondialdehyde (MDA) content in rat brain homogenates. When mice were administered an intraperitoneal injection of LPS alone, mortality occurred from 4 to 16 h, after which time all were dead. However, eugenosedin-A significantly prolonged the survival time after LPS injection, suggesting that eugenosedin-A protected against LPS-induced cardiovascular dysfunction, hyperglycaemia, tissue injury and inflammatory cytokine production. This was attributable mainly to the antioxidant and peroxyl radical scavenged effects of eugenosedin-A, and which may be, at least in part, due to its blockade on alpha/beta-adrenergic and serotonergic receptors.

Topics: Animals; Antidepressive Agents, Second-Generation; Antioxidants; Aorta, Thoracic; Blood Glucose; Cytokines; Free Radical Scavengers; Hyperglycemia; Hypotension; In Vitro Techniques; Lipid Peroxidation; Lipopolysaccharides; Mice; Mice, Inbred ICR; Oxidants; Oxidative Stress; Peroxides; Piperazines; Rats; Rats, Wistar; Survival Analysis; Trazodone