Effect of alpha-mangostin on olanzapine-induced metabolic disorders in rats

Document Type : Original Article


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): As olanzapine has side effects such as weight gain and metabolic disorders, and alpha-mangostin has been shown to control metabolic disorders, the effects of alpha-mangostin on metabolic disorders induced by olanzapine were investigated in this study.
Materials and Methods: Obesity was induced in female Wistar rats by daily administration of olanzapine (5 mg/kg/day, IP, 14 days). Rats were divided into 6 groups:1) vehicle (control); 2) olanzapine (5 mg/kg/day); 3,4,5) olanzapine+ alpha-mangostin (10, 20, 40 mg/kg/day, IP); 6) alpha-mangostin (40 mg/kg/day). Weight changes were measured every 3 days and food intake was assessed every day. Systolic blood pressure, plasma levels of blood sugar, triglycerides, total cholesterol, HDL, LDL, leptin, oxidative stress markers (MDA, GSH), AMPK, and P-AMPK protein levels in liver tissue were assessed on the last day of the study. 
Results: Administration of olanzapine significantly increased weight gain, food intake, blood pressure, triglycerides, LDL, blood sugar, leptin, and MDA in rat liver tissue and also decreased GSH, AMPK, and P-AMPK in liver tissue compared with the control group. Different doses of alpha-mangostin significantly reduced weight gain, food intake, systolic blood pressure, triglycerides, LDL, blood sugar, leptin, and MDA. Also, they significantly increased GSH, AMPK, and P-AMPK in liver tissue compared with the olanzapine group.
Conclusion: Olanzapine increases leptin levels, food intake, and weight, induces oxidative stress, decreases the levels of AMPK and P-AMPK proteins in liver tissue, and causes metabolic disorders. But, alpha-mangostin reduces the negative effects of olanzapine by activation of AMPK. 


1. Mollazadeh H, Hosseinzadeh H. Cinnamon effects on metabolic syndrome: a review based on its mechanisms. Iran J Basic Med Sci 2016; 19:1258–1270.
2. Razavi BM, Abazari AR, Rameshrad M, Hosseinzadeh H. Carnosic acid prevented olanzapine-induced metabolic disorders through AMPK activation. Mol Biol Rep 2020; 47:7583-7592.
3. Baradaran Rahimi V, Askari VR, Hosseinzadeh H. Promising influences of Scutellaria baicalensis and its two active constituents, baicalin, and baicalein, against metabolic syndrome: A review. Phytother Res 2021; 35:3558-3574.
4. Dehghani S, Mehri S, Hosseinzadeh H. The effects of Crataegus pinnatifida (Chinese hawthorn) on metabolic syndrome: A review. Iran J Basic Med Sci 2019; 22:460-468.
5. Esmaeilzadeh D, Razavi BM, Hosseinzadeh H. Effect of Abelmoschus esculentus (okra) on metabolic syndrome: A review. Phytother Res 2020; 34:2192-2202.
6. Galavi A, Hosseinzadeh H, Razavi BM. The effects of Allium cepa L.(onion) and its active constituents on metabolic syndrome: A review. Iran J Basic Med Sci 2021; 24:3-16.
7. Eisvand F, Razavi BM, Hosseinzadeh H. The effects of Ginkgo biloba on metabolic syndrome: A review. Phytother Res 2020; 34:1798-1811.
8. Hassani FV, Shirani K, Hosseinzadeh H. Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:931-949.
9. Mahdian D, Abbaszadeh-Goudarzi K, Raoofi A, Dadashizadeh G, Abroudi M, Zarepour E, et al. Effect of Boswellia species on the metabolic syndrome: A review. Iran J Basic Med Sci 2020; 23:1374-1381.
10. Bhana N, Foster RH, Olney R, Plosker GL. Olanzapine. Drugs 2001; 61:111-161.
11. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951-962.
12. Coccurello R, Caprioli A, Conti R, Ghirardi O, Borsini F, Carminati P, et al. Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2, 3-b][1, 5] benzodiazepine), but not the novel atypical antipsychotic ST2472 (9-piperazin-1-ylpyrrolo [2, 1-b][1, 3] benzothiazepine), chronic administration induces weight gain, hyperphagia, and metabolic dysregulation in mice. J Pharmacol Exp Ther 2008; 326:905-911.
13. Chen C-H, Shyue S-K, Hsu C-P, Lee T-S. Atypical antipsychotic drug olanzapine deregulates hepatic lipid metabolism and aortic inflammation and aggravates atherosclerosis. Cell Physiol Biochem 2018; 50:1216-1229.
14. Razavi BM, Lookian F, Hosseinzadeh H. Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats. Biomed Pharmacother 2017; 92:726-731.
15. Coccurello R, Moles A. Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design. Pharmacol  Therapeut 2010; 127:210-251.
16. Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H. Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacol 2007; 32:289-297.
17. Boyda H, Procyshyn R, Tse L, Wong D, Pang C, Honer W, et al. Intermittent treatment with olanzapine causes sensitization of the metabolic side-effects in rats. Neuropharmacol 2012; 62:1391-1400.
18. Weston-Green K, Huang X-F, Lian J, Deng C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol 2012; 22:364-373.
19. Boyda HN, Tse L, Procyshyn RM, Wong D, Wu TK, Pang CC, et al. A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:945-954.
20. Rojo LE, Gaspar PA, Silva H, Risco L, Arena P, Cubillos-Robles K, et al. Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacology. Pharmacol Res 2015; 101:74-85.
21. Lieberman J. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators; effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209-1223.
22. Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S, et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res 2009; 110:103-110.
23. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis 2006; 3:A42.
24. Malekzadeh S, Heidari MR, Razavi BM, Rameshrad M, Hosseinzadeh H. Effect of safranal, a constituent of saffron, on olanzapine (an atypical antipsychotic) induced metabolic disorders in rat. Iran J Basic Med Sci 2019; 22:1476-1482.
25. Patil BM, Kulkarni NM, Unger BS. Elevation of systolic blood pressure in an animal model of olanzapine induced weight gain. Eur J Pharmacol 2006; 551:112-115.
26. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A 2007; 104:3456-3459.
27. Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 2008; 14:539-549.
28. Macmillan HF. Tropical planting and gardening with sepcial reference to ceylon: Asian Educational Services; 1999.
29. Wahyono S, Astuti P, Artaama W. Characterisation of a bioactive substance and mangostin isolated from the hull of Garicinia mangostana Indones. J Pharmacol 1999; 10:127-134.
30. Yaacob O, Tindall HD. Mangosteen cultivation: Food & Agriculture Org.; 1995.
31. Schmid W. Ueber das mangostin. Justus Liebigs Ann Chem 1855; 93:83-88.
32. Dragendorff O. Ueber das harz von Garcinia mangostana L. Justus Liebigs Ann Chem 1930; 482:280-301.
33. Gutierrez-Orozco F, Chitchumroonchokchai C, Lesinski GB, Suksamrarn S, Failla ML. α-Mangostin: anti-inflammatory activity and metabolism by human cells. J Agric Food Chem 2013; 61:3891-3900.
34. Ibrahim MY, Hashim NM, Mariod AA, Mohan S, Abdulla MA, Abdelwahab SI, et al. α-Mangostin from Garcinia mangostana Linn: an updated review of its pharmacological properties. Arab J Chem 2016; 9:317-329.
35. Ibrahim MY, Hashim NM, Mohan S, Abdulla MA, Abdelwahab SI, Kamalidehghan B, et al. Involvement of nF-κB and hsP70 signaling pathways in the apoptosis of MDa-MB-231 cells induced by a prenylated xanthone compound, α-mangostin, from Cratoxylum arborescens. Drug Des Devel Ther 2014; 8:2193–2211.
36. Márquez-Valadez B, Maldonado PD, Galván-Arzate S, Méndez-Cuesta LA, Pérez-De La Cruz V, Pedraza-Chaverrí J, et al. Alpha-mangostin induces changes in glutathione levels associated with glutathione peroxidase activity in rat brain synaptosomes. Nutr Neurosci 2012; 15:13-19.
37. Tousian Shandiz H, Razavi BM, Hosseinzadeh H. Review of Garcinia mangostana and its xanthones in metabolic syndrome and related complications. Phytother Res 2017; 31:1173-1182.
38. Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the ameliorative effect of alpha‐mangostin on development and existing pain in a rat model of neuropathic pain. Phytother Res 2020; 34:3211-3225.
39. Tousian H, Razavi BM, Hosseinzadeh H. Effects of alpha-mangostin on memory senescence induced by high glucose in human umbilical vein endothelial cells. Iran J Basic Med Sci 2020; 23:1261-1267.
40. Tousian H, Razavi BM, Hosseinzadeh H. Alpha-mangostin decreased cellular senescence in human umbilical vein endothelial cells. Daru 2019; 28:45-55.
41. Choi YH, Bae JK, Chae H-S, Kim Y-M, Sreymom Y, Han L, et al. α-Mangostin regulates hepatic steatosis and obesity through SirT1-AMPK and PPARγ pathways in high-fat diet-induced obese mice. J Agric Food Chem 2015; 63:8399-8406.
42. Jariyapongskul A, Areebambud C, Suksamrarn S, Mekseepralard C. Alpha-mangostin attenuation of hyperglycemia-induced ocular hypoperfusion and blood retinal barrier leakage in the early stage of type 2 diabetes rats. Biomed Res Int 2015; 2015:785826.
43. Soetikno V, Murwantara A, Prisma Andini FC, Gilbert Lazarus ML, Arozal W. Alpha-mangostin improves cardiac hypertrophy and fibrosis and associated biochemical parameters in high-fat/high-glucose diet and low-dose streptozotocin injection-induced type 2 diabetic rats. J Exp Pharmacol 2020; 12:27-38.
44. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983; 16:109-110.
45. Lee C-H, Ying T-H, Chiou H-L, Hsieh S-C, Wen S-H, Chou R-H, et al. Alpha-mangostin induces apoptosis through activation of reactive oxygen species and ASK1/p38 signaling pathway in cervical cancer cells. Oncotarget 2017; 8:47425-47439.
46. Larson RT, Lorch JM, Pridgeon JW, Becnel JJ, Clark GG, Lan Q. The biological activity of α-mangostin, a larvicidal botanic mosquito sterol carrier protein-2 inhibitor. J Med Entomol 2014; 47:249-257.
47. Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86:271-278.
48. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82:70-77.
49. Taher M, Mohamed Amiroudine MZA, Tengku Zakaria TMFS, Susanti D, Ichwan SJ, Kaderi MA, et al. α-Mangostin improves glucose uptake and inhibits adipocytes differentiation in 3T3-L1 cells via PPARγ, GLUT4, and leptin expressions. Evid Based Complement Alternat Med 2015; 2015:740238.
50. Jain S, Bhargava M, Gautam S. Weight gain with olanzapine: Drug, gender or age? Indian J Psychiatry 2006; 48:39-42.
51. Mathews J, Newcomer JW, Mathews JR, Fales CL, Pierce KJ, Akers BK, et al. Neural correlates of weight gain with olanzapine. Arch Gen Psychiatry 2012; 69:1226-1237.
52. Cunningham JI, Eyerman DJ, Todtenkopf MS, Dean RL, Deaver DR, Sanchez C, et al. Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates. J Psychopharmacol 2019; 33:1303-1316.
53. Esteghamati A, Noshad S, Khalilzadeh O, Morteza A, Nazeri A, Meysamie A, et al. Contribution of serum leptin to metabolic syndrome in obese and nonobese subjects. Arch Med Res 2011; 42:244-251.
54. Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M. Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol 2002; 22:424-426.
55. Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, et al. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 2006; 20:75-79.
56. Myers Jr MG, Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 2010; 21:643-651.
57. Salviato Balbão M, Cecílio Hallak JE, Arcoverde Nunes E, Homem de Mello M, Triffoni-Melo AdT, Ferreira FIdS, et al. Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up. Ther Adv Psychopharmacol 2014; 4:30-36.
58. Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 1999; 60:767-770.
59. Kumar V, Bhatt PC, Kaithwas G, Rashid M, Al-Abbasi F, Khan JA, et al. α-Mangostin mediated pharmacological modulation of hepatic carbohydrate metabolism in diabetes induced Wistar rat. Beni-Seuf Univ J Appl Sci 2016; 5:255-276.
60. Kunwar A, Priyadarsini K. Free radicals, oxidative stress and importance of antioxidants in human health. J Med Allied Sci 2011; 1:53-60.
61. Koltas IS, Yucebilgic G, Bilgin R, Parsak CK, Sakman G. Serum malondialdehyde level in patients with cystic echinococcosis. Saudi Med J 2006; 27:1703-1705.
62. Fernández-Sánchez A, Madrigal-Santillán E, Bautista M, Esquivel-Soto J, Morales-González Á, Esquivel-Chirino C, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci 2011; 12:3117-3132.
63. Ahmed S, Maher F, Naji N. Effect of leptin and oxidative stress in the blood of obese individuals. Biochem Trends Endocrinol Metab 2010;11:643-651.
64. An H, Du X, Huang X, Qi L, Jia Q, Yin G, et al. Obesity, altered oxidative stress, and clinical correlates in chronic schizophrenia patients. Transl Psychiatry 2018; 8:1-7.
65. Eftekhari A, Azarmi Y, Parvizpur A, Eghbal MA. Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes. Xenobiotica 2016; 46:369-378.
66. Lestari N, Pratama S, Gotama KT, Soetikno V, Louisa M. Antioxidative activity of alpha-mangostin in acetaldehyde-induced hepatic stellate cells: An in vitro study. Int J App Pharm 2019; 11:164-167.
67. Yan X-t, Sun Y-s, Ren S, Zhao L-c, Liu W-c, Chen C, et al. Dietary α-mangostin provides protective effects against acetaminophen-induced hepatotoxicity in mice via Akt/mTOR-mediated inhibition of autophagy and apoptosis. Int J Mol Sci 2018; 19:1335.
68. Kola B. Role of AMP‐activated protein kinase in the control of appetite. J Neuroendocrinol 2008; 20:942-951.
69. He M, Zhang Q, Deng C, Wang H, Lian J, Huang X-F. Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats. Psychoneuroendocrinology 2014; 42:153-164.