European Review for Medical and Pharmacological Sciences 2011; 15: 1187-1195 Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats: comparison to sibutramine D.M. ABO-ELMATTY, S.A. ZAITONE* Department of Biochemistry and *Department of Pharmacology and Toxicology; Faculty of Pharmacy, Suez Canal University, Ismailia (Egypt) Abstract. – Background and Objectives: BP = Blood pressure Topiramate is newly approved as anticonvulsant DBP = Diastolic blood pressure that seems to promote body weight loss in hu- FAs = Fatty acids mans. The present study was designed to evalu- FDA = Food and Drugs Administration ate the weight-controlling properties of topiramate in dietary obese female rats in comparison with HDL-C = High density lipoprotein cholesterol sibutramine. HFD = High fat diet Materials and Methods: Fifty rats were as- HOMA-IR index = Homeostasis model assess- signed as normal, high fat diet (HFD), HFD + sibu- ment insulin resistance in- tramine (7.5 mg/kg, p.o.), HFD + topiramate (25 dex mg/kg, p.o.) and HFD + topiramate (50 mg/kg, LDL-C = Low density lipoprotein cholesterol p.o.). Body weight was registered, anxiety was NPD = Normal palatable diet tested in Vogel’s test and blood pressure (BP) was measured. In addition, liver index, adipose tissue R-QUICKI = Revised quantitative insulin sen- index, fasting blood glucose and serum lipid pro- sitivity check index file were measured in all groups. Further, serum SBP = Systolic blood pressure insulin, leptin and adiponectin were determined. TAG = Triacylglycerol Results: Feeding with HFD induced a significant TC = Total cholesterol increase in body weight of rats as well as insulin resistance and serum lipids as compared to nor- mal group (p<0.05). These measurements were suppressed by sibutramine treatment. However, a significant elevation in BP and anxiety behavior Introduction were detected as compared with HFD group (p<0.05). Topiramate (50 mg/kg, p.o.) group The current obesity pandemic imposes a major showed weight loss, improved insulin resistance, global disease burden. The rise in obesity will be lessened anxiety behavior without influence on BP. accompanied by increases in related disorders Discussion: Our data ensures the findings that topiramate has a weight controlling properties such as diabetes, hypertension and heart 1 with no anxiogenic or hypertensive effects. Fur- diseases . Obesity has been traditionally chal- ther investigations are needed to determine the lenged with diets, exercise and behavioral modi- utility of topiramate in the clinical management of fication. These techniques have still so far failed obesity. to halt the obesity pandemic. Given the enormity of the obesity problem, adjunctive pharmacother- Key Words: apy provides an attractive solution2. However, Obesity, Topiramate, Weight control, Anxiety, Blood very few drugs have been developed for obesity Pressure. treatment and those that are approved have only limited success1. When sibutramine was received approval from Abbreviations the American Food and Drugs Administration (FDA) in November of 1997, it represented the AMPA = α-amino-3-hydroxy-5-methyl-4- first unique agent of a new class of medications isoxazolepropionic acid for the treatment of obesity. Sibutramine is a Corresponding Author: Sawsan A. Zaitone, Ph.D; e-mail: [email protected] 1187 D.M. Abo-Elmatty, S.A. Zaitone pharmacological agent with selective norepi- NPD for five months; the remaining rats received nephrine, serotonin and a lesser extent, HFD for three months to establish diet-induced dopamine, reuptake inhibitor3. Cardiovascular obesity. Table I illustrates the formula of the diet: side effects include an increase in systolic and di- it provides 17% energy as carbohydrates, 25% as astolic BP, and an increase in heart rate, tachy- protein, and 58% as fat as a percentage of total cardia and palpitations. These adrenergic side ef- kcal/g10. Rats receiving HFD were divided equal- fects are a particular concern for patients with ly into four groups. One group returned to nor- hypertension. Additionally, an increase appear- mal diet and the other groups returned to normal ance of mood-related disorders has been reported diet and treated with sibutramine (7.5 mg/kg/day, during sibutramine treatment such as insomnia4 p.o.)11 or topiramate (25 mg/kg/day, p.o.) or topi- and generalized anxiety and panic disorders5. ramate (50 mg/kg/day, p.o.)12 for additional two However, in October of 2010, sibutramine was months. The changes in body weight were moni- removed from the US market due to an evident tored every week. The animals were cared for in increased risk of heart attack and stroke. After accordance with the principles and guidelines of withdrawal of sibutramine, only one medication- the Canadian Council on care and use of experi- orlistat-has been approved by the FDA for long- mental animals. All experimental procedures fol- term use in the treatment of obesity6. Reported lowed were in accordance with guidelines of the side effects of orlistat include flatus with dis- Institutional Animal Care and Use Committee. charge and oily stool. Severe problems such as fecal urgency, incontinence and abdominal pain Drugs can also occur2. The adverse effects of these Sibutramine hydrochloride (Medical Union agents highlighted a continued need for safe and Pharmaceuticals, Ismailia, Egypt) was dissolved effective medications for the treatment of obesity in distilled water and administered orally. Topira- with a positive impact on health related quality mate (Delta Pharm, 10th of Ramadan City, Egypt) of life. was dissolved in 2% tween-80 solution. Topiramate is a structurally novel therapeutic agent currently approved for marketing as an Testing Anxiety in Vogel’s Proconflict antiepileptic drug. Topiramate has been reported Situation Test to exert multiple pharmacological effects that Briefly, after 24 hrs of water deprivation, each may determine its broad range of activities in- rat was placed in the cage of the anxiometer. The cluding anticonvulsant, analgesic, and mood-sta- cage is a Plexiglas box (25×25×25 cm) equipped bilizing properties7. Topiramate has been report- with a grid floor of stainless steel bars and a ed to cause a decrease in body weight in some drinking bottle containing water (Anxiometer epileptic patients during clinical evaluation8. Model, LE 3206, Panlab s.l., Barcelona, Spain) These observations prompted studies to elucidate was used for training and testing for animals the mechanistic basis of topiramate induced where it was given an opportunity to consume weight loss in animals9. Therefore, the present study was designed for evaluation of the weight controlling properties of Table I. Composition of the high fat diet. topiramate in dietary obese rats in comparison with sibutramine. Further, we aimed to explore Amount the role of improving insulin resistance or regula- Ingredients (g/kg)e tion of adipokines in this pharmacological effect. Powdered NPD1 365 Lard2 310 Casein3 250 4 Materials and Methods Cholesterol 10 Vitamin and mineral mix5 60 DL-Methionine6 03 Animals and Experimental Design Yeast powder7 01 Fifty female albino rats were housed in stan- 8 dard cages and maintained under controlled room Sodium chloride 01 temperature (25 ± 3) and normal light-dark cycle 1,2,7,8Purchased from the market; 3Difco (Becton Dickinson, with free access to food and water. Rats had ini- France), 4Oxford Lab, Mumbai, India; 5,6Sigma-Aldrich, tial body weight 150-180 g. Ten rats received MO, USA; 8ADWIC Co., Cairo, Egypt. 1188 Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats water from a drinking bottle. A sharp decrease high HOMA index denotes low insulin sensitivi- of the number of drinking episodes testifies to ty23. To assess insulin sensitivity, another derived the existence of anxiety and increased fear in an- index was suggested, i.e., the revised quantitative imal13,14. insulin sensitivity check index (R-QUICKI) = [1/log fasting insulin (μU/ml) + log fasting glu- Measuring Systemic Arterial cose (mg/dl)]24. Blood Pressure Rats were deeply anaesthetized with thiopental Statistical Analysis sodium (40 mg/kg, i.p.)15 and placed on a temper- The results are expressed as mean ± SEM. The ature-controlled panel. A laparotomy was per- data was analyzed using Statistical Package of formed and a non-occlusive, polyvinyl catheter Social Sciences (SPSS) program version 16, was implanted in the abdominal aorta, caudal to Chicago, IL, USA. One-way analysis of vari- the kidneys, through a puncture wound in the ance, ANOVA, followed by Bonferroni’s multi- aortic wall made with the tip of an L-shaped 18- ple comparisons test were employed for statisti- gauge needle. The catheter was fixed by tying a cal analysis. A value of p≤0.05 was considered to ligature. The arterial catheter was filled with he- be statistically significant. parin solution (1.000 USP U/ml)16 and connected to digital BP monitor (Columbus Instruments, OHIO, 43204, USA) for BP recording. Mean systolic BP (SBP) and diastolic BP (DBP) were Results measured for each group. Body Weight Gain, Liver Index and Blood Sampling and Adipose Tissue Index Biochemical Analysis In the current study, HFD group showed a sig- After measuring the BP, blood samples were nificant increase in the percentage body weight collected by cardiac puncture. Serum was sepa- gain as compared to NPD group (53 ± 6 vs. 17 ± rated and kept at –80°C until performing the bio- 2 g, respectively, p≤0.05, Table II). Treatment chemical measurements. Serum insulin was de- with sibutramine (7.5 mg/kg/day, p.o.) for two termined using ultra sensitive rat insulin ELISA months significantly reduced percentage body kit (Crystal Chem Inc., Downers Grove, IL weight gain to 31 ± 3 g (p≤0.05). Similarly, treat- 60515, USA)17. Serum leptin was measured by ment with the high dose of topiramate (50 rat leptin ELISA kit (Crystal Chem Inc., USA)18. mg/kg/day, p.o.) reduced the percentage weight Serum adiponectin was detected by rat gain value significantly to 36 ± 5 g as compared adiponectin ELISA kit (AdipoGen Inc.