J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 281-291, 2006 281 Anti-Hyperlipidemic and Hypoglycemic Effects of Gynostemma pentaphyllum in the Zucker Fatty Rat Samer Megalli, Neal M. Davies, and Basil D. Roufogalis Faculty of Pharmacy and Herbal Medicines Research and Education Centre University of Sydney, Building Al5, Sydney NSW 2006. Received May 20, 2006; Revised July 19, 2006; Accepted Aug 3, 2006; Published, September 30, 2006. ______________________________________ ABSTRACT - Gynostemma pentaphyllum is a traditional Chinese medicine used for a variety of conditions, including elevated cholesterol. We have examined the pharma-cological anti-hyperlipidemic and hypoglycemic effectiveness of Gynostemma pentaphyllum in the obese Zucker fatty diabetic rat model. After treatment for 4 days Gynostemma pentaphyllum 250 mg/kg reduced triglyceride (33%), total cholesterol, (13%) and low density lipoprotein cholesterol levels (33%). These effects were dose-dependent and maintained for at least 5 weeks. Chronic treatment for 3-5 weeks also reduced post-prandial hypertriglyceridemia induced by olive oil 10 mg/kg in the Zucker fatty rats but had no significant effect in lowering sucrose-induced hyper- glycemia in Sprague-Dawley rats. A novel regulation by Gynostemma of glucose levels was also observed in the Zucker fatty rat model. In a glucose tolerance test in obese and lean Zucker rats pretreatment with Gynostemma pentaphyllum 250 mg/kg demonstrated glucose levels were significantly less 2 hours post challenge (20%) in the Gynostemma pentaphyllum obese rats compared to the control group. Gynostemma pentaphyllum did not significantly reduce glucose levels at 120 min in the lean strain, in contrast to the 20% decrease seen in the obese rat. In vitro, Gynostemma penta- phyllum inhibited α-glucosidase activity (50% inhibition at 42.8), which compared to acarbose (50% at 53.9 µg/mL). The improvement in glucose tolerance at 120 min by Gynostemma pentaphyllum in obese Zucker fatty rats but not lean rats suggests that it may improve insulin receptor sensitivity and together with the significant reduction of hyper- triglyceridemia, cholesterol and low density liporprotein cholesterol suggests that Gynostemma should be examined further by oral hypoglycemic / anti-hyperlipidemic therapy. INTRODUCTION Gynostemma pentaphylum (GP) has been used traditionally in Chinese medicine for its anti- inflammatory, anti-cancer and cardiovascular properties. It contains more than 90 saponins, including gynosaponins that have been isolated and identified in Asia and suggested to have a variety of pharmacological properties. (Zhou 1988; Zhang et al. 1993). We have previously demonstrated that GP demonstrates anti-inflammatory properties in murine macrophages and anti-hyperlipidemic properties in a polaxamer-P407 induced hyper- lipidemic rat model. (Aktan et al. 2003; Megalli et al. 2005; Huang et al. 2006). In addition we have further identified a novel LXR-a activator (TR1) in GP that selectively enhanced ABCA1 and apoE gene expression (Huang et al. 2005) LXR plays an important role in cholesterol homeostasis. Recently a novel insulin releasing substance, phanoside has also been isolated from GP.(Norberg et al. 2004). Zucker fatty rats have been widely used as a model for obesity studies. Homozygous obese Zucker rats (fa/fa) are characterized by hype- rglycemia, hyperinsulinemia, hyperphagy, glucose intolerance, hypersecretion of insulin after glucose feeding, low glucagon secretion, hyper- triglyceridemia and hypercholesterolemia. In particular, very low density lipoproteins (VLDL) and high-density lipoproteins (HDL) are increased (Phillips et al. 1996). This model differs from the P407 rat model, in which the increase in tri- glycerides is mainly attributed to the inhibition of endothelial LPL (Johnston and Palmer 1993). Obese Zucker rats are used as a model for type-2 diabetes mellitus. In the present study, the Zucker fatty rat model was used to investigate the characteristics of anti-hyperlipidemic and anti-diabetic effect of GP in this genetic model. In addition the effect of GP on sucrose and glucose tolerance was also investigated in Sprague-Dawley rats. Possible mechanisms of GP anti-hyperlipidemia and hypoglycemia are described using these models. _________________________________________ Corresponding Author: Dr. Sam Megalli, Faculty of Pharmacy Pharmacy, The University of Sydney, NSW 2006, Australia. Tel: +61 2 93512726 Fax: +61 2 93514391 smegalli@pharm.usyd.edu.au