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Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats
Biomedicine & Pharmacotherapy 92 (2017) 726–731
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Original article
Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats Bibi Marjan Razavia , Fariba Lookianb , Hossein Hosseinzadehc,* a Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran c Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
A R T I C L E I N F O
Article history: Received 25 March 2017 Received in revised form 16 May 2017 Accepted 24 May 2017 Keywords: Olanzapine Green tea Camellia sinensis Metabolic syndrome Weight gain Leptin
A B S T R A C T
Atypical antipsychotics particularly olanzapine are associated with obesity and serious metabolic disturbances. As green tea (Camellia sinensis) is generally associated with beneficial effects on obesity and other metabolic disturbances, this study was undertaken to evaluate the effect of green tea aqueous extract (GTAE) on olanzapine induced weight gain and metabolic abnormalities in rats. Male Wistar rats were divided into eight groups: control, olanzapine (5 mg/kg/day, IP.), GTAE (25, 50 and 100 mg/kg/day, IP.) plus olanzapine and GTAE (25, 50 and 100 mg/kg/day, IP.). Treatments were continued for 11 days. Body weight gain, average food and water intake were measured during the experiment. Plasma lipid, glucose and leptin levels, mean systolic blood pressure and total locomotion were evaluated at the end of experiment. Olanzapine induced significant weight gain at the end of treatment (10.38% of body weight) when compared to control (3.13% of body weight) in male Wistar rats. Average food and water intake were increased by olanzapine treatment. 11 days olanzapine administration led to hyperleptinemia, hyperglycemia and dyslipidemia. Olanzapine also increased mean systolic blood pressure and decreased total locomotion. GTAE decreased significantly body weight gain and average food and water intake, improved the changes in lipid profile as well as fasting blood glucose, and finally decreased hyperleptinemia and hypertension induced by olanzapine. Results of this study demonstrated that GTAE could exert protective effects against olanzapine induced obesity partially due to its lowering effect on leptin. GTAE improved other metabolic abnormalities including dyslipidemia, hyperglycemia and hypertension induced by olanzapine in rats. © 2017 Published by Elsevier Masson SAS.
1. Introduction Atypical antipsychotics are the first line medications for acute and maintenance therapy of schizophrenia, because of better tolerability and medication compliance when compared with conventional antipsychotics [1]. However, accumulating evidence suggests that many atypical antipsychotics particularly olanzapine and clozapine are associated with serious metabolic disturbances, such as weight gain, insulin resistance, blood glucose abnormalities and hyperlipidemia which can increase risks for developing metabolic and cardiovascular diseases in patients with schizophrenia and can lead to decreased quality of life in patients with mental illness [2,3]. The incidence of metabolic syndrome after
* Corresponding author. E-mail address: [email protected] (H. Hosseinzadeh). http://dx.doi.org/10.1016/j.biopha.2017.05.113 0753-3322/© 2017 Published by Elsevier Masson SAS.
atypical antipsychotic treatment was reported to be 20–60%, which is at least twofold the incidence rate in the general population [4]. Although exact mechanisms of antipsychotic–induced weight gain and metabolic disturbances are not yet fully elucidated, however, the proposed mechanisms underlying antipsychoticinduced weight gain include D2 receptor antagonism, H1 receptor antagonism, muscarinic (M3) receptor antagonism, 5-HT2C receptor antagonism or inverse agonist [5,6] and HTR2C and HTR2A gene polymorphisms [7]. Moreover, a reduction of physical activity [8], an increase in food intake, increased appetite and insulin resistance seem to be associated with the occurrence of metabolic abnormalities induced by olanzapine [9]. Green tea, produced from the unfermented dried leaves of the plant Camellia sinensis, has been consumed by humans worldwide, especially in East Asian countries [10]. Green tea contains caffeine and polyphenolic compounds known as catechins. Catechins are a
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class of low molecular weight polyphenols which consist mainly of flavan-3-ol monomers [11]. The most important catechins are ( )-epigallocatechin-3gallate (EGCG), ( )-epigallocatechin (EGC), ( )-epicatechin-3gallate (ECG) and ( )-epicatechin (EC). Among them, EGCG is the most abundant catechin found in green tea and has been suggested to be responsible for many of the potential health effects of green tea particularly antioxidant properties [11,12]. Regular drinking of green tea has been associated with many health benefits on lipid profile, blood glucose levels, cancer, hypertension and weight loss [11,13]. Protective effects of green tea and its main constituents against natural and chemical toxins have been shown [14]. In addition, tea consumption reduces the risk of cardiovascular diseases and metabolic syndrome [15]. Strategies for management antipsychotic induced weight gain have been of limited success, emphasizing the need to further investigation [16]. Several plants and their active components such as Vitis vinifera [17], Nigella sativa [18], Allium sativum [19], Rosmarinus officinalis [20], Crocus sativus [21], Persea americana [22], Cinnamomum verum [23], thymoquinone [18] and rutin [24] are being used for the therapy of different disorders including metabolic syndrome due to their safety, efficacy, cultural acceptability and lesser side effects. As green tea is generally associated with beneficial effects on obesity and other metabolic disturbances, the attraction of using green tea extract as therapeutic agents in olanzapine induced weight gain and metabolic abnormalities is considerable.
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approved by the ethical committee (No:920801) of Mashhad University of Medical Sciences. Rats were randomly divided into eight groups. Control (distilled water, IP.), olanzapine (5 mg/kg/day, IP.), GTAE (25, 50 and 100 mg/kg/day, IP.) plus olanzapine, and GTAE (25, 50 and 100 mg/kg/day, IP.) groups. Treatments were continued for 11 days. The dose for olanzapine was determined from previous studies with some modifications [27]. Food consumption and body weights were measured daily. Daily food intake was calculated as the difference in the amount of food placed in the hopper and that remaining 24 h later, less the amount recovered as spillage. To evaluate the effect of olanzapine on motor activity and mean systolic blood pressure open field test [9] and non-invasive tail cuff method [28] were used respectively at the end of experiment. After 11 days, all rats were killed by decapitation, and trunk blood collected and serum was separated. Total cholesterol, LDL-C, HDLC, TG and glucose levels were determined using enzymatic kits. Serum leptin level (Leptin Rat ELISA Kit; ab100773, United States) was also measured at the end of experiment. 2.5. Statistical analysis Data are expressed as mean SEM. One way and two-way ANOVA followed by Tukey–Kramer and Bonferroni post hoc tests, respectively, were performed to compare means. P values less than 0.05 were considered as significant. 3. Results
2. Materials and methods
3.1. Total polyphenol content of green tea
2.1. Chemicals
The total phenolic content was 50 mg/g of dry weight of extract, expressed as gallic acid equivalents.
Olanzapine (Hetero drugs limited, India), Folin reagent (Fluka, Germany), sodium carbonate (Sigma, Germany) and galic Acid (Sigma, Germany) were obtained. 2.2. Preparation of green tea aqueous extracts (GTAE) Green tea leaves were collected from North of Iran. The leaves were powdered using a milling machine. 100 g of green tea powder was macerated in 1000 mL of boiling water for 15 min. Then the extract was centrifuged at 3000 g for 7 min after filtration and the supernatants were pooled and then lyophilized [25].
3.2. Body weight In male Wistar rats, olanzapine treatment induced significant weight gain. As shown in Fig. 1, olanzapine induced significant weight gain at the end of treatment (10.38% of body weight, 24 g) when compared to vehicle treatment (3.13% of body weight, 7 g).
2.3. Determination of total polyphenol content of green tea extract Total amount of phenolic compounds has been estimated by Folin-Ciocalteu reagent using the standard gallic acid calibration curve. The method was based on the reduction of phosphotungstic acid in alkaline solution to phosphotungstic blue [26]. Briefly, 0.5 mL of GTAE was mixed with 4.5 mL distilled water. Then 0.2 mL Folin-Ciocalteu phenol reagent and 0.5 mL of 20% sodium carbonate solution was added to the mixture, which was then shaken thoroughly and diluted to 10 mL by adding distilled water. The mixture was incubated for 60 min and blue color formed was measured at 725 nm using a spectrophotometer. A calibration curve of gallic acid was prepared and the results were expressed as mg gallic acid equivalents per gram of dried weight of the tea. 2.4. Animals Adult male Wistar rats, weighing 230 20 g, were provided by Animal House, School of Pharmacy, Mashhad University of Medical Sciences, Iran. Rats were housed singly in standard plastic cages in the colony room under 12-h light/dark cycle, 22 2 C and 40–50% humidity and had free access to food and water. This study was
Fig. 1. Effect of olanzapine and green tea on body weight gain during treatment. *P < 0.05 and ** P < 0.01 vs control group, # P < 0.05, ## P < 0.01 and ### P < 0.001 vs olanzapine group. Two-way ANOVA followed by Bonferroni post-hoc test for multiple comparisons. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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Significant increase in body weight was observed at 10th and 11th days of treatment with 5 mg/kg olanzapine compared to vehicle (Fig. 1). GTAE (50 mg/kg) significantly reduced body weight gain induced by olanzapine at 9th to 11th days of study. A significant reduction of body weight gain induced by olanzapine was also observed at 7th to 11th days of study with GTAE (100 mg/kg). 3.3. Food and water intake Average food and water intake in rats treated with olanzapine was significantly increased compared to vehicle treated rats (P < 0.01) (Fig. 2A and B). Results showed that GTAE (25, 50 and 100 mg/kg) decreased average food intake during 11 days treatment compared to the vehicle group. Coadministration of GTAE (25, 50 and 100 mg/kg) with olanzapine significantly reduced the increase of food and water intake induced by olanzapine (P < 0.001). 3.4. Plasma glucose, triglyceride, and lipid profiles As shown in Table 1, olanzapine treatment significantly increased the blood glucose (191%), LDL-C (39%), TG (83%) and total cholesterol (30%) and decreased HDL-C (19%) compared to the control. GTAE (25, 50 and 100 mg/kg) significantly decreased blood glucose, LDL-C, TG and total cholesterol and increased HDL-C when compared with the olanzapine group. 3.5. Motor activity and mean systolic blood pressure Olanzapine treatment significantly decreased total locomotion (TL) compared to control. Coadministration of GTAE (25, 50 and 100 mg/kg) with olanzapine significantly increased the decrease of motor activity induced by olanzapine (P < 0.001) (Fig. 3). As shown in Fig. 4, olanzapine treatment increased mean systolic blood pressure significantly as compared to vehicle treated groups at the end of experiment. Blood pressure among the groups before initiation of the treatment did not differ (data not shown). Coadministration of GTAE (25, 50 and 100 mg/kg) significantly caused a reduction of 13%, 15% and 20%, respectively in mean systolic blood pressure when compared with the olanzapine group.
3.6. Plasma leptin level According to the results, olanzapine treatment caused approximately three fold increase in plasma leptin level compared with control group. GTAE (25, 50 and 100 mg/kg) significantly reduced the increase in plasma leptin induced by olanzapine (P < 0.001) (Fig. 5). Moreover, plasma leptin level was increased by GTAE (25 and 50 mg/kg) administration. 4. Discussion Antipsychotic-induced metabolic disorders are the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus resulting in increased morbidity and mortality. Some strategies for the management of antipsychotic-induced metabolic side effects such as obesity include life style change and pharmaceutical intervention [29]. Because anorexigenic drugs were predicted to be unsafe, especially for patients treated with psychotropic medications [16], so, many efforts have been continuing for the development of adjunctive therapy to prevent the metabolic abnormalities induced by antipsychotics such as olanzapine. Green tea is believed to be used as a popular beverage to prevent the development of obesity and metabolic syndrome [15]. In this study, the effect of green tea on weight gain and metabolic disturbances associated with olanzapine has been evaluated in male Wistar rat. The underlying mechanisms of olanzapineinduced weight gain are incompletely understood. To study this, we administered olanzapine (5 mg/kg/day, IP.) in male Wistar rats for 11 days. Food and water intake, locomotor activity and plasma leptin level were evaluated. Olanzapine is reported to increase weight gain in several clinical and animal studies [30,31]. A recent meta-analysis study identified that olanzapine induced more weight gain in patients with schizophrenia, compared to other antipsychotics drugs [32]. Another study revealed that female Sprague–Dawley rats receiving olanzapine (1.2 mg/kg/day) via gavage for 10 days showed significant increases in body weight compared to the control rats. Food intake in the olanzapine group was significantly increased at 6 th to 10 th days of treatment. Olanzapine also increased food intake efficiency (grams of weight gained/grams of food consumed). Results of this study also showed that gross motor activity was
Fig. 2. Effect of olanzapine and green tea on average food (A) and water (B) intake. * P < 0.05 and *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple comparisons.
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Table 1 Effect of olanzapine and green tea on plasma glucose and lipid profile. *P < 0.05 and ***P < 0.001 vs control group, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
FBS (mg/dl) LDL-C (mg/dl). HDL-C (mg/dl) Total Cholesterol (mg/dl) TG (mg/dl)
Control
Olanzapine 5 mg/kg
GTAE 25 mg/kg
GTAE 50 mg/kg
GTAE 100 mg/kg
Olanzapine + GTAE 25 mg/kg
Olanzapine + GTAE 50 mg/kg
Olanzapine + GTAE 100 mg/kg
84 2.65 40 1.03 31 1.69 66 0.89
247 5.26*** 56 2.63*** 25 1.37*** 86 1.16***
126 3.05*** 49 2.12*** 32 1.78 86 1.34***
106 2.86*** 37 1.48 30 1.14 65 1.51
76 2.38*** 36 2.4* 28 1.41* 62 0.83***
165 1.87### 56 2.4 26 1.22 82 0.83###
156 3.39### 51 1.51## 28 1.30# 75 1.34###
132 2.07### 45 1.14### 31 0.89### 72 1.00###
66 2.13
122 2.25***
76 2.16***
65 2.38
54 2.38***
116 2.38##
106 2.38###
96 2.58###
Fig. 3. Effect of olanzapine and green tea on total locomotion (TL) at the end of treatment (11 th day). *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
Fig. 4. Effect of olanzapine and green tea on mean systolic blood pressure at the end of treatment (11 th day). *P < 0.05 and *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
significantly decreased by olanzapine during treatment [30]. Our results demonstrated that olanzapine administration induced body weight gain and elevated average food and water intake during 11 days of treatment compared to vehicle group. Although
some studies reported that olanzapine administration could induce weight gain in female, but not male rats [33], in this study olanzapine induced significant weight gain at the end of the drug treatment (10.38% of body weight) when compared to vehicle treatment (3.13% of body weight) in male Wistar rats. This discrepancy was due to the several factors including differences between dosage of olanzapine, route of administration and strains of animals [33]. Increasing evidence showed that decreased motor activity due to the sedative effects of antipsychotics could be considered as one of the mechanisms of olanzapine induced weight gain [30]. Similarly, results of open field test showed that olanzapine markedly decreased total locomotion after 11 days treatment compared to the control group. It has been proposed that changes in adipocytokines secreted by adipocytes such as leptin are believed to be involved in weight gain induced by olanzapine [34]. Leptin has a role in weight regulation by effect on food intake, energy consumption, and glycolipid metabolism [35]. In obese people the amount of leptin increased and weight loss led to the decrease of leptin level. Studies indicated that weight gain induced by olanzapine was associated with an increase of plasma leptin level [36]. Results of this study revealed that olanzapine significantly increased plasma leptin level after 11 days treatment. Taken together, olanzapine (5 mg/kg, IP.) after 11 days treatment, induced weight gain due to the increased appetite (food and water consumption), decreased motor activity and increased plasma leptin level in male Wistar rats. According to documents, other mechanisms including increased feed efficiency and insulin resistance [37] and activated hypothalamic AMPK [38] are also might be involved in olanzapine induced weight gain. In addition, the data suggested that GTAE has significant effects on preventing olanzapine induced weight gain in this rat model. There are several studies describing the beneficial effects of green tea and its constituents in obesity. For examples, the results of randomized controlled trials indicated that the administration of green tea catechins with caffeine is associated with statistically significant reductions in body mass index, body weight and waist circumference after 12 weeks [39]. Another study showed that EGCG (3.2 g/kg diet) significantly reduced body weight after 16 weeks in high fat–induced obesity, in mice [40]. This study also indicated that GTAE reduced average food and water consumption and caused a reduction in the level of plasma leptin compared with olanzapine group. These results are inconsistent with the results of another study which indicated the administration of diets containing 2 and 4% green tea powder remarkably suppressed body weight gain, plasma leptin level and food intake in female ICR mice after 16 weeks treatment [41]. Our data also showed that decreased motor activity induced by olanzapine was reversed by GTAE coadministration. Our results are not in agreement with other study which showed oral administration of 0.6% green tea to SKH-1 mice for 15 weeks increased total 24 h locomotor activity [42]. This may be due to the
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various animal and clinical studies [46,47] antidiabetic effects of green tea and its polyphenols could be also attributed to different mechanisms. It has been identified that EGCG dysregulated hepatic glucose production and possessed insulin-like effects, so that, it can increase tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it can affect several insulin-activated kinases with slower kinetics [48,49]. Furthermore, green tea modulated glucose metabolism [50] and improved cytokine-induced pancreatic beta-cell damage [51]. The inhibition of sodium-dependent glucose transporter (SGLT1) which is responsible for intestinal glucose uptake by green tea has been shown in another study [52]. The antihypertensive effects of GTAE have been shown in our study. Our results are in agreement with other studies which indicated daily supplementation with 379 mg of green tea extract decreased systolic and diastolic blood pressure, insulin resistance, inflammation and oxidative stress, and improved lipid profile in patients with obesity-related hypertension [53]. The antihypertensive effects of green tea may be related to decrease insulin resistance and its anti-obesity effects. 5. Conclusion Fig. 5. Effect of olanzapine and green tea on plasma leptin level. *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
several factors including different route of exposure, different period of study and different animal specious. In addition to increase the risk of obesity, it was established that some antipsychotics such as olanzapine have a high tendency to cause metabolic abnormalities. Therefore these drugs increase the risk of metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease [43]. Metabolic syndrome is a disorder associated with obesity, high blood glucose, dyslipidemia and high blood pressure [44]. Results of this study showed that GTAE exhibits preventive effects against olanzapine induced weight gain. Furthermore, in this study, the role of green tea in other components of metabolic syndrome induced by olanzapine including high blood pressure, dyslipidemia and high blood glucose has been evaluated. Our results showed that olanzapine significantly increased fasting blood glucose (FBS), induced dyslipidemia as evidenced by increased LDL-C, TG and total cholesterol and decreased HDL-C, and increased systolic blood pressure compared with control group. Coadministeration of GTAE with olanzapine restored these factors. Numerous studies reported that atypical antipsychotic treatment is associated with metabolic changes in serum glucose and lipid, insulin resistance and hyperinsulinemia due to the different mechanisms including impaired tissue glucose uptake, pancreatic beta-cell damage, impaired leptin action, weight gain and adiposity [45]. Moreover, obesity and hyperinsulinemia induced by olanzapine led to the development of hypertension [28]. The protective effects of green tea as well as its polyphenols such as EGCG on metabolic syndrome have been established [15]. It has been reported that EGCG, the most abundant green tea polyphenols, significantly reduced hyperglycemia, insulin resistance and hypercholesterolemia in high-fat–fed mice. In addition, EGCG treatment attenuated the effects of high-fat diet on blood glucose. The beneficial effects of ECGC on metabolic adverse effects induced by high-fat diet may be attributed to different mechanisms including decreased fat absorption, antioxidant and antiinflammatory effects, decreased fatty acid synthesis and increased fatty acid oxidation [40]. In addition, according to
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Original article
Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats Bibi Marjan Razavia , Fariba Lookianb , Hossein Hosseinzadehc,* a Targeted Drug Delivery Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran c Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
A R T I C L E I N F O
Article history: Received 25 March 2017 Received in revised form 16 May 2017 Accepted 24 May 2017 Keywords: Olanzapine Green tea Camellia sinensis Metabolic syndrome Weight gain Leptin
A B S T R A C T
Atypical antipsychotics particularly olanzapine are associated with obesity and serious metabolic disturbances. As green tea (Camellia sinensis) is generally associated with beneficial effects on obesity and other metabolic disturbances, this study was undertaken to evaluate the effect of green tea aqueous extract (GTAE) on olanzapine induced weight gain and metabolic abnormalities in rats. Male Wistar rats were divided into eight groups: control, olanzapine (5 mg/kg/day, IP.), GTAE (25, 50 and 100 mg/kg/day, IP.) plus olanzapine and GTAE (25, 50 and 100 mg/kg/day, IP.). Treatments were continued for 11 days. Body weight gain, average food and water intake were measured during the experiment. Plasma lipid, glucose and leptin levels, mean systolic blood pressure and total locomotion were evaluated at the end of experiment. Olanzapine induced significant weight gain at the end of treatment (10.38% of body weight) when compared to control (3.13% of body weight) in male Wistar rats. Average food and water intake were increased by olanzapine treatment. 11 days olanzapine administration led to hyperleptinemia, hyperglycemia and dyslipidemia. Olanzapine also increased mean systolic blood pressure and decreased total locomotion. GTAE decreased significantly body weight gain and average food and water intake, improved the changes in lipid profile as well as fasting blood glucose, and finally decreased hyperleptinemia and hypertension induced by olanzapine. Results of this study demonstrated that GTAE could exert protective effects against olanzapine induced obesity partially due to its lowering effect on leptin. GTAE improved other metabolic abnormalities including dyslipidemia, hyperglycemia and hypertension induced by olanzapine in rats. © 2017 Published by Elsevier Masson SAS.
1. Introduction Atypical antipsychotics are the first line medications for acute and maintenance therapy of schizophrenia, because of better tolerability and medication compliance when compared with conventional antipsychotics [1]. However, accumulating evidence suggests that many atypical antipsychotics particularly olanzapine and clozapine are associated with serious metabolic disturbances, such as weight gain, insulin resistance, blood glucose abnormalities and hyperlipidemia which can increase risks for developing metabolic and cardiovascular diseases in patients with schizophrenia and can lead to decreased quality of life in patients with mental illness [2,3]. The incidence of metabolic syndrome after
* Corresponding author. E-mail address: [email protected] (H. Hosseinzadeh). http://dx.doi.org/10.1016/j.biopha.2017.05.113 0753-3322/© 2017 Published by Elsevier Masson SAS.
atypical antipsychotic treatment was reported to be 20–60%, which is at least twofold the incidence rate in the general population [4]. Although exact mechanisms of antipsychotic–induced weight gain and metabolic disturbances are not yet fully elucidated, however, the proposed mechanisms underlying antipsychoticinduced weight gain include D2 receptor antagonism, H1 receptor antagonism, muscarinic (M3) receptor antagonism, 5-HT2C receptor antagonism or inverse agonist [5,6] and HTR2C and HTR2A gene polymorphisms [7]. Moreover, a reduction of physical activity [8], an increase in food intake, increased appetite and insulin resistance seem to be associated with the occurrence of metabolic abnormalities induced by olanzapine [9]. Green tea, produced from the unfermented dried leaves of the plant Camellia sinensis, has been consumed by humans worldwide, especially in East Asian countries [10]. Green tea contains caffeine and polyphenolic compounds known as catechins. Catechins are a
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class of low molecular weight polyphenols which consist mainly of flavan-3-ol monomers [11]. The most important catechins are ( )-epigallocatechin-3gallate (EGCG), ( )-epigallocatechin (EGC), ( )-epicatechin-3gallate (ECG) and ( )-epicatechin (EC). Among them, EGCG is the most abundant catechin found in green tea and has been suggested to be responsible for many of the potential health effects of green tea particularly antioxidant properties [11,12]. Regular drinking of green tea has been associated with many health benefits on lipid profile, blood glucose levels, cancer, hypertension and weight loss [11,13]. Protective effects of green tea and its main constituents against natural and chemical toxins have been shown [14]. In addition, tea consumption reduces the risk of cardiovascular diseases and metabolic syndrome [15]. Strategies for management antipsychotic induced weight gain have been of limited success, emphasizing the need to further investigation [16]. Several plants and their active components such as Vitis vinifera [17], Nigella sativa [18], Allium sativum [19], Rosmarinus officinalis [20], Crocus sativus [21], Persea americana [22], Cinnamomum verum [23], thymoquinone [18] and rutin [24] are being used for the therapy of different disorders including metabolic syndrome due to their safety, efficacy, cultural acceptability and lesser side effects. As green tea is generally associated with beneficial effects on obesity and other metabolic disturbances, the attraction of using green tea extract as therapeutic agents in olanzapine induced weight gain and metabolic abnormalities is considerable.
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approved by the ethical committee (No:920801) of Mashhad University of Medical Sciences. Rats were randomly divided into eight groups. Control (distilled water, IP.), olanzapine (5 mg/kg/day, IP.), GTAE (25, 50 and 100 mg/kg/day, IP.) plus olanzapine, and GTAE (25, 50 and 100 mg/kg/day, IP.) groups. Treatments were continued for 11 days. The dose for olanzapine was determined from previous studies with some modifications [27]. Food consumption and body weights were measured daily. Daily food intake was calculated as the difference in the amount of food placed in the hopper and that remaining 24 h later, less the amount recovered as spillage. To evaluate the effect of olanzapine on motor activity and mean systolic blood pressure open field test [9] and non-invasive tail cuff method [28] were used respectively at the end of experiment. After 11 days, all rats were killed by decapitation, and trunk blood collected and serum was separated. Total cholesterol, LDL-C, HDLC, TG and glucose levels were determined using enzymatic kits. Serum leptin level (Leptin Rat ELISA Kit; ab100773, United States) was also measured at the end of experiment. 2.5. Statistical analysis Data are expressed as mean SEM. One way and two-way ANOVA followed by Tukey–Kramer and Bonferroni post hoc tests, respectively, were performed to compare means. P values less than 0.05 were considered as significant. 3. Results
2. Materials and methods
3.1. Total polyphenol content of green tea
2.1. Chemicals
The total phenolic content was 50 mg/g of dry weight of extract, expressed as gallic acid equivalents.
Olanzapine (Hetero drugs limited, India), Folin reagent (Fluka, Germany), sodium carbonate (Sigma, Germany) and galic Acid (Sigma, Germany) were obtained. 2.2. Preparation of green tea aqueous extracts (GTAE) Green tea leaves were collected from North of Iran. The leaves were powdered using a milling machine. 100 g of green tea powder was macerated in 1000 mL of boiling water for 15 min. Then the extract was centrifuged at 3000 g for 7 min after filtration and the supernatants were pooled and then lyophilized [25].
3.2. Body weight In male Wistar rats, olanzapine treatment induced significant weight gain. As shown in Fig. 1, olanzapine induced significant weight gain at the end of treatment (10.38% of body weight, 24 g) when compared to vehicle treatment (3.13% of body weight, 7 g).
2.3. Determination of total polyphenol content of green tea extract Total amount of phenolic compounds has been estimated by Folin-Ciocalteu reagent using the standard gallic acid calibration curve. The method was based on the reduction of phosphotungstic acid in alkaline solution to phosphotungstic blue [26]. Briefly, 0.5 mL of GTAE was mixed with 4.5 mL distilled water. Then 0.2 mL Folin-Ciocalteu phenol reagent and 0.5 mL of 20% sodium carbonate solution was added to the mixture, which was then shaken thoroughly and diluted to 10 mL by adding distilled water. The mixture was incubated for 60 min and blue color formed was measured at 725 nm using a spectrophotometer. A calibration curve of gallic acid was prepared and the results were expressed as mg gallic acid equivalents per gram of dried weight of the tea. 2.4. Animals Adult male Wistar rats, weighing 230 20 g, were provided by Animal House, School of Pharmacy, Mashhad University of Medical Sciences, Iran. Rats were housed singly in standard plastic cages in the colony room under 12-h light/dark cycle, 22 2 C and 40–50% humidity and had free access to food and water. This study was
Fig. 1. Effect of olanzapine and green tea on body weight gain during treatment. *P < 0.05 and ** P < 0.01 vs control group, # P < 0.05, ## P < 0.01 and ### P < 0.001 vs olanzapine group. Two-way ANOVA followed by Bonferroni post-hoc test for multiple comparisons. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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Significant increase in body weight was observed at 10th and 11th days of treatment with 5 mg/kg olanzapine compared to vehicle (Fig. 1). GTAE (50 mg/kg) significantly reduced body weight gain induced by olanzapine at 9th to 11th days of study. A significant reduction of body weight gain induced by olanzapine was also observed at 7th to 11th days of study with GTAE (100 mg/kg). 3.3. Food and water intake Average food and water intake in rats treated with olanzapine was significantly increased compared to vehicle treated rats (P < 0.01) (Fig. 2A and B). Results showed that GTAE (25, 50 and 100 mg/kg) decreased average food intake during 11 days treatment compared to the vehicle group. Coadministration of GTAE (25, 50 and 100 mg/kg) with olanzapine significantly reduced the increase of food and water intake induced by olanzapine (P < 0.001). 3.4. Plasma glucose, triglyceride, and lipid profiles As shown in Table 1, olanzapine treatment significantly increased the blood glucose (191%), LDL-C (39%), TG (83%) and total cholesterol (30%) and decreased HDL-C (19%) compared to the control. GTAE (25, 50 and 100 mg/kg) significantly decreased blood glucose, LDL-C, TG and total cholesterol and increased HDL-C when compared with the olanzapine group. 3.5. Motor activity and mean systolic blood pressure Olanzapine treatment significantly decreased total locomotion (TL) compared to control. Coadministration of GTAE (25, 50 and 100 mg/kg) with olanzapine significantly increased the decrease of motor activity induced by olanzapine (P < 0.001) (Fig. 3). As shown in Fig. 4, olanzapine treatment increased mean systolic blood pressure significantly as compared to vehicle treated groups at the end of experiment. Blood pressure among the groups before initiation of the treatment did not differ (data not shown). Coadministration of GTAE (25, 50 and 100 mg/kg) significantly caused a reduction of 13%, 15% and 20%, respectively in mean systolic blood pressure when compared with the olanzapine group.
3.6. Plasma leptin level According to the results, olanzapine treatment caused approximately three fold increase in plasma leptin level compared with control group. GTAE (25, 50 and 100 mg/kg) significantly reduced the increase in plasma leptin induced by olanzapine (P < 0.001) (Fig. 5). Moreover, plasma leptin level was increased by GTAE (25 and 50 mg/kg) administration. 4. Discussion Antipsychotic-induced metabolic disorders are the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus resulting in increased morbidity and mortality. Some strategies for the management of antipsychotic-induced metabolic side effects such as obesity include life style change and pharmaceutical intervention [29]. Because anorexigenic drugs were predicted to be unsafe, especially for patients treated with psychotropic medications [16], so, many efforts have been continuing for the development of adjunctive therapy to prevent the metabolic abnormalities induced by antipsychotics such as olanzapine. Green tea is believed to be used as a popular beverage to prevent the development of obesity and metabolic syndrome [15]. In this study, the effect of green tea on weight gain and metabolic disturbances associated with olanzapine has been evaluated in male Wistar rat. The underlying mechanisms of olanzapineinduced weight gain are incompletely understood. To study this, we administered olanzapine (5 mg/kg/day, IP.) in male Wistar rats for 11 days. Food and water intake, locomotor activity and plasma leptin level were evaluated. Olanzapine is reported to increase weight gain in several clinical and animal studies [30,31]. A recent meta-analysis study identified that olanzapine induced more weight gain in patients with schizophrenia, compared to other antipsychotics drugs [32]. Another study revealed that female Sprague–Dawley rats receiving olanzapine (1.2 mg/kg/day) via gavage for 10 days showed significant increases in body weight compared to the control rats. Food intake in the olanzapine group was significantly increased at 6 th to 10 th days of treatment. Olanzapine also increased food intake efficiency (grams of weight gained/grams of food consumed). Results of this study also showed that gross motor activity was
Fig. 2. Effect of olanzapine and green tea on average food (A) and water (B) intake. * P < 0.05 and *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple comparisons.
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Table 1 Effect of olanzapine and green tea on plasma glucose and lipid profile. *P < 0.05 and ***P < 0.001 vs control group, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
FBS (mg/dl) LDL-C (mg/dl). HDL-C (mg/dl) Total Cholesterol (mg/dl) TG (mg/dl)
Control
Olanzapine 5 mg/kg
GTAE 25 mg/kg
GTAE 50 mg/kg
GTAE 100 mg/kg
Olanzapine + GTAE 25 mg/kg
Olanzapine + GTAE 50 mg/kg
Olanzapine + GTAE 100 mg/kg
84 2.65 40 1.03 31 1.69 66 0.89
247 5.26*** 56 2.63*** 25 1.37*** 86 1.16***
126 3.05*** 49 2.12*** 32 1.78 86 1.34***
106 2.86*** 37 1.48 30 1.14 65 1.51
76 2.38*** 36 2.4* 28 1.41* 62 0.83***
165 1.87### 56 2.4 26 1.22 82 0.83###
156 3.39### 51 1.51## 28 1.30# 75 1.34###
132 2.07### 45 1.14### 31 0.89### 72 1.00###
66 2.13
122 2.25***
76 2.16***
65 2.38
54 2.38***
116 2.38##
106 2.38###
96 2.58###
Fig. 3. Effect of olanzapine and green tea on total locomotion (TL) at the end of treatment (11 th day). *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
Fig. 4. Effect of olanzapine and green tea on mean systolic blood pressure at the end of treatment (11 th day). *P < 0.05 and *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
significantly decreased by olanzapine during treatment [30]. Our results demonstrated that olanzapine administration induced body weight gain and elevated average food and water intake during 11 days of treatment compared to vehicle group. Although
some studies reported that olanzapine administration could induce weight gain in female, but not male rats [33], in this study olanzapine induced significant weight gain at the end of the drug treatment (10.38% of body weight) when compared to vehicle treatment (3.13% of body weight) in male Wistar rats. This discrepancy was due to the several factors including differences between dosage of olanzapine, route of administration and strains of animals [33]. Increasing evidence showed that decreased motor activity due to the sedative effects of antipsychotics could be considered as one of the mechanisms of olanzapine induced weight gain [30]. Similarly, results of open field test showed that olanzapine markedly decreased total locomotion after 11 days treatment compared to the control group. It has been proposed that changes in adipocytokines secreted by adipocytes such as leptin are believed to be involved in weight gain induced by olanzapine [34]. Leptin has a role in weight regulation by effect on food intake, energy consumption, and glycolipid metabolism [35]. In obese people the amount of leptin increased and weight loss led to the decrease of leptin level. Studies indicated that weight gain induced by olanzapine was associated with an increase of plasma leptin level [36]. Results of this study revealed that olanzapine significantly increased plasma leptin level after 11 days treatment. Taken together, olanzapine (5 mg/kg, IP.) after 11 days treatment, induced weight gain due to the increased appetite (food and water consumption), decreased motor activity and increased plasma leptin level in male Wistar rats. According to documents, other mechanisms including increased feed efficiency and insulin resistance [37] and activated hypothalamic AMPK [38] are also might be involved in olanzapine induced weight gain. In addition, the data suggested that GTAE has significant effects on preventing olanzapine induced weight gain in this rat model. There are several studies describing the beneficial effects of green tea and its constituents in obesity. For examples, the results of randomized controlled trials indicated that the administration of green tea catechins with caffeine is associated with statistically significant reductions in body mass index, body weight and waist circumference after 12 weeks [39]. Another study showed that EGCG (3.2 g/kg diet) significantly reduced body weight after 16 weeks in high fat–induced obesity, in mice [40]. This study also indicated that GTAE reduced average food and water consumption and caused a reduction in the level of plasma leptin compared with olanzapine group. These results are inconsistent with the results of another study which indicated the administration of diets containing 2 and 4% green tea powder remarkably suppressed body weight gain, plasma leptin level and food intake in female ICR mice after 16 weeks treatment [41]. Our data also showed that decreased motor activity induced by olanzapine was reversed by GTAE coadministration. Our results are not in agreement with other study which showed oral administration of 0.6% green tea to SKH-1 mice for 15 weeks increased total 24 h locomotor activity [42]. This may be due to the
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various animal and clinical studies [46,47] antidiabetic effects of green tea and its polyphenols could be also attributed to different mechanisms. It has been identified that EGCG dysregulated hepatic glucose production and possessed insulin-like effects, so that, it can increase tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it can affect several insulin-activated kinases with slower kinetics [48,49]. Furthermore, green tea modulated glucose metabolism [50] and improved cytokine-induced pancreatic beta-cell damage [51]. The inhibition of sodium-dependent glucose transporter (SGLT1) which is responsible for intestinal glucose uptake by green tea has been shown in another study [52]. The antihypertensive effects of GTAE have been shown in our study. Our results are in agreement with other studies which indicated daily supplementation with 379 mg of green tea extract decreased systolic and diastolic blood pressure, insulin resistance, inflammation and oxidative stress, and improved lipid profile in patients with obesity-related hypertension [53]. The antihypertensive effects of green tea may be related to decrease insulin resistance and its anti-obesity effects. 5. Conclusion Fig. 5. Effect of olanzapine and green tea on plasma leptin level. *** P < 0.001 vs control group, ### P < 0.001 vs olanzapine group. Data are reported as mean SEM (n = 6). One-way ANOVA followed by Tukey-Kramer post-hoc test for multiple.
several factors including different route of exposure, different period of study and different animal specious. In addition to increase the risk of obesity, it was established that some antipsychotics such as olanzapine have a high tendency to cause metabolic abnormalities. Therefore these drugs increase the risk of metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease [43]. Metabolic syndrome is a disorder associated with obesity, high blood glucose, dyslipidemia and high blood pressure [44]. Results of this study showed that GTAE exhibits preventive effects against olanzapine induced weight gain. Furthermore, in this study, the role of green tea in other components of metabolic syndrome induced by olanzapine including high blood pressure, dyslipidemia and high blood glucose has been evaluated. Our results showed that olanzapine significantly increased fasting blood glucose (FBS), induced dyslipidemia as evidenced by increased LDL-C, TG and total cholesterol and decreased HDL-C, and increased systolic blood pressure compared with control group. Coadministeration of GTAE with olanzapine restored these factors. Numerous studies reported that atypical antipsychotic treatment is associated with metabolic changes in serum glucose and lipid, insulin resistance and hyperinsulinemia due to the different mechanisms including impaired tissue glucose uptake, pancreatic beta-cell damage, impaired leptin action, weight gain and adiposity [45]. Moreover, obesity and hyperinsulinemia induced by olanzapine led to the development of hypertension [28]. The protective effects of green tea as well as its polyphenols such as EGCG on metabolic syndrome have been established [15]. It has been reported that EGCG, the most abundant green tea polyphenols, significantly reduced hyperglycemia, insulin resistance and hypercholesterolemia in high-fat–fed mice. In addition, EGCG treatment attenuated the effects of high-fat diet on blood glucose. The beneficial effects of ECGC on metabolic adverse effects induced by high-fat diet may be attributed to different mechanisms including decreased fat absorption, antioxidant and antiinflammatory effects, decreased fatty acid synthesis and increased fatty acid oxidation [40]. In addition, according to
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