Effect of safranal, a constituent of saffron, on olanzapine (an atypical antipsychotic) induced metabolic disorders in rat

Document Type : Original Article

Authors

1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

3 Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

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

5 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran

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

Abstract

Objective(s): Olanzapine, an atypical antipsychotic, causes weight gain and metabolic disorders in humans. Safranal, one of the active components of Crocus sativus (saffron), has been shown to have anti-obesity, lipid and blood pressure lowering and anti-diabetes effects. In this investigation, the effect of safranal on metabolic disorders induced by olanzapine was studied.
Materials and Methods: Fourty-two female Wistar rats were divided into 7 groups of 6 animals. The two groups were selected as controls, which received olanzapine and safranal solvents, respectively. The third group treated by olanzapine 5 mg/kg. Groups 4, 5 and 6 treated by olanzapine 5 mg/kg plus safranal (2.5, 5 and 10 mg/kg) and the last group received safranal 10 mg/kg. The injections were performed intraperitoneally for 14 days and on the 15th day the rats were killed and their serum were collected to measure metabolic factors including glucose, insulin, triglyceride, total cholesterol and HDL cholesterol. Leptin level in plasma was also measured. Mean systolic blood pressure was measured using tail cuff method at the end of study. The rats were weighed every other day and amount of food consumed was measured daily.
Results: Olanzapine significantly elevated body weight, food intake, fasting blood glucose, TG, leptin, and mean systolic blood pressure (MSBP). It also significantly decreased HDL cholesterol blood level. Safranal significantly improved all these complications at three doses.
Conclusion: Based on the results of this study, safranal is thought to be used as an effective combination in controlling metabolic complications caused by olanzapine.

Keywords

References

1. Newcomer JW. Metabolic risk during antipsychotic treatment. Clin Ther 2004; 26:1936-1946.
2. Lozano P, Delgado D, Gomez D, Rubio M, Iborra JL. A non-destructive method to determine the safranal content of saffron (Crocus sativus L.) by supercritical carbon dioxide extraction combined with high-performance liquid chromatography and gas chromatography. J Biochem Biophys Methods 2000; 43:367-378.
3. Perez-Iglesias R, Crespo-Facorro B, Amado JA, Garcia-Unzueta MT, Ramirez-Bonilla ML, Gonzalez-Blanch C, et al. A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive, first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone. J Clin Psychiatry 2007; 68:1733-1740.
4. 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.
5. Ejtahed HS, Tabatabaei-Malazy O, Soroush AR, Hasani-Ranjbar S, Siadat SD, Raes J, et al. Worldwide trends in scientific publications on association of gut microbiota with obesity. Iran J Basic Med Sci 2019; 22:65-71.
6. Girault EM, Alkemade A, Foppen E, Ackermans MT, Fliers E, Kalsbeek A. Acute peripheral but not central administration of olanzapine induces hyperglycemia associated with hepatic and extra-hepatic insulin resistance. PLoS One 2012; 7:e43244.
7. Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang RH, Nasrallah HA. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63:920-930.
8. Gianfrancesco F, White R, Wang RH, Nasrallah HA. Antipsychotic-induced type 2 diabetes: evidence from a large health plan database. J Clin Psychopharmacol 2003; 23:328-335.
9. Lambert BL, Chou CH, Chang KY, Tafesse E, Carson W. Antipsychotic exposure and type 2 diabetes among patients with schizophrenia: a matched case-control study of California Medicaid claims. Pharmacoepidemiol Drug Saf 2005; 14:417-425.
10. Hu Y, Young AJ, Ehli EA, Nowotny D, Davies PS, Droke EA, et al. Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS One 2014; 9:e93310.
11. Razavi B, Lookian F, Hosseinzadeh H. Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats. Biomed Pharmacother 2017; 92:726-731.
12. Lian J, Huang XF, Pai N, Deng C. Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment. PLoS One 2014; 9:e104160.
13. Mizuno Y, Suzuki T, Nakagawa A, Yoshida K, Mimura M, Fleischhacker WW, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2014; 40:1385-1403.
14. Belanoff JK, Blasey CM, Clark RD, Rao RL. Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats. Eur J Pharmacol 2011; 25:117-120.
15. Wallingford N, Sinnayah P, Bymaster F, Gadde K, Krishnan R, McKinney A, et al. Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 2008; 33:2922-2933.
16. Razavi BM, Hosseinzadeh H. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric 2017; 97:1679-1685.
17. Akaberi M, Hosseinzadeh H. Grapes (Vitis vinifera) as a Potential Candidate for the Therapy of the Metabolic Syndrome. Phytother Res 2016; 30:540-556.
18. Rameshrad M, Razavi BM, Imenshahidi M, Hosseinzadeh H. Vitis vinifera (grape) seed extract and resveratrol alleviate bisphenol-A-induced metabolic syndrome: Biochemical and molecular evidences. Phytother Res 2019; 33:832-844.
19. Razavi B, Hosseinzadeh H. A review of the effects of Nigella sativa L. and its constituent, thymoquinone, in metabolic syndrome. J Endocrinol Invest 2014; 37:1031-1040.
20. Hosseini A, Hosseinzadeh H. A review on the effects of Allium sativum (Garlic) in metabolic syndrome. J Endocrinol Invest 2015; 38:1147-1157.
21. Hassani F, 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.
22. Tabeshpour J, Razavi B, Hosseinzadeh H. Effects of avocado (Persea americana) on metabolic syndrome: A comprehensive systematic review. Phytother Res 2017; 31:819-837.
23. Mollazadeh H, Hosseinzadeh H. Cinnamon effects on metabolic syndrome: a review based on its mechanisms. Iran J Basic Med Sci 2016; 19:1258-1270.
24. Hosseinzadeh H, Nassiri-Asl M. Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Invest 2014; 37:783-788.
25. Srivastava R, Ahmed H, Dixit RK, Dharamveer, Saraf SA. Crocus sativus L.: A comprehensive review. Pharmacogn Rev 2010; 4:200-208.
26. Gohari A, Saeidnia S, Mahmoodabadi M. An overview on saffron, phytochemicals, and medicinal properties. Pharmacogn Rev 2013; 7:61-66.
27. Hosseini A, Razavi BM, Hosseinzadeh H. Saffron (Crocus sativus) petal as a new pharmacological target: a review. Iran J Basic Med Sci 2018;21:1091-1099.
28.  Rezaee-Khorasany A, Razavi BM, Taghiabadi E, Tabatabaei Yazdi A, Hosseinzadeh H. Effect of saffron (stigma of Crocus sativus L.) aqueous extract on ethanol toxicity in rats: A biochemical, histopathological and molecular study. J Ethnopharmacol  2019 12; 286-299.
29. Hosseinzadeh H, Karimi G, Niapoor M. Antidepressant effect of Crocus sativus L. stigma extracts and their constituents, crocin and safranal, in mice. Acta Hortic 2004;650.
30. Hosseinzadeh H, Sadeghnia H. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci 2005; 8:394-399.
31. Rezaee R, Hosseinzadeh H. Safranal: from an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 2013; 16:12-26.
32. Zeinali M, Zirak MR, Rezaee SA, Karimi G, Hosseinzadeh H. Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review. Iran J Basic Med Sci 2019; 22:334-344.
33. Bharti S, Golechha M, Kumari S, Siddiqui K, Arya D. Akt/GSK-3beta/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia-reperfusion injury in rats. Eur J Nutr 2012; 51:719-727.
34. Imenshahidi M, Razavi BM, Faal A, Gholampoor A, Mousavi SM, Hosseinzadeh H. The effect of chronic administration of safranal on systolic blood pressure in rats. Iran J Pharm Res 2015; 14:585-590.
35. Kianbakht S, Hajiaghaee R. Anti-hyperglycemic effects of saffron and its active constituents, crocin and safranal, in alloxan-induced diabetic rats. J Med Plants 2011; 3:82-89.
36. Samarghandian S, Azimi-Nezhad M, Samini F. Ameliorative effect of saffron aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic encephalopathy in streptozotocin induced experimental diabetes mellitus. Biomed Res Int 2014; 2014:920857.
37. Dehghan F, Hajiaghaalipour F, Yusof A, Muniandy S, Hosseini SA, Heydari S, et al. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in vitro and in vivo. Sci Rep 2016; 6:25139.
38. Mollazadeh H, Mahdian D, Hosseinzadeh H. Medicinal plants in treatment of hypertriglyceridemia: A review based on their mechanisms and effectiveness. Phytomedicine 2018; 53:43-52.
39. Jassim G, Skrede S, Vazquez MJ, Wergedal H, Vik-Mo AO, Lunder N, et al. Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat. Psychopharmacology (Berl) 2012; 219:783-794.
40. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, et al. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 2006; 14:36-51.
41. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156:1686-1696.
42. Arjona AA, Zhang SX, Adamson B, Wurtman RJ. An animal model of antipsychotic-induced weight gain. Behav Brain Res 2004; 152:121-127.
43. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003; 28:519-526.
44. Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, et al. Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring) 2010; 18:1646-1651.
45. Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, et al. Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study. J Clin Psychopharmacol 2007; 27:662-666.
46. 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.
47. Tagami K, Kashiwase Y, Yokoyama A, Nishimura H, Miyano K, Suzuki M, et al. The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor. Neuropeptides 2016; 58:93-101.
48. Bergman RN, Ader M. Atypical antipsychotics and glucose homeostasis. J Clin Psychiatry 2005; 66:504-514.
49. Kim BJ, Sohn JW, Park CS, Hahn GH, Koo J, Noh YD, et al. Body weight and plasma levels of ghrelin and leptin during treatment with olanzapine. J Korean Med Sci 2008; 23:685-690.
50. Murashita M, Kusumi I, Inoue T, Takahashi Y, Hosoda H, Kangawa K, et al. Olanzapine increases plasma ghrelin level in patients with schizophrenia. Psychoneuroendocrinology 2005; 30:106-110.
51. Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999; 156:312-314.
52. Prolo P, Wong M, Licinio J. Leptin. Int J Biochem Cell Biol 1998; 30:1285-1290.
53. Janeckova R. The role of leptin in human physiology and pathophysiology. Physiol Res 2001; 50:443-459.
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. Atmaca M, Tezcan E, Ustundag B. Plasma nitric oxide and leptin values in patients with olanzapine-induced weight gain. J Psychiatric Res 2007; 41:74-79.
56. Gout B, Bourges C, Paineau-Dubreuil S. Satiereal, a Crocus sativus L extract, reduces snacking and increases satiety in a randomized placebo-controlled study of mildly overweight, healthy women. Nutr Res 2010; 30:305-313.
57. Razi M. Al-Hawi fi’l-tibb (Comprehensive book of medicine). Hyderabad: Osmania Oriental Publications Bureau 1968; 20:548-553.
58. Maeda A, Kai K, Ishii M, Ishii T, Akagawa M. Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK-Ay mice. Mol Nutr Food Res 2014; 58:1177-1189.
59. Konstantopoulos P, Doulamis IP, Tzani A, Korou ML, Agapitos E, Vlachos IS, et al. Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats. Biomed Rep 2017; 6:513-518.
60. Mashmoul M, Azlan A, Mohtarrudin N, Nisak B, Yusof M, Khaza’ai H. Saffron extract and crocin reduced biomarkers associated with obesity in rats fed a high-fat diet. Mal J Nutr 20017; 23: 117-127.
61. Hosseinzadeh H, Mehri S, Abolhassani MM, Ramezani M, Sahebkar A, Abnous K. Affinity-based target deconvolution of safranal. Daru 2013; 21:25.
62. Hazman O, Ovali S. Investigation of the anti-inflammatory effects of safranal on high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Inflammation 2015; 38:1012-1019.
63. Graham K, Perkins D, Edwards L, Barrier R, Lieberman J, Harp J. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry 2005; 162:118-123.
64. Teff K, Kim S. Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol Behav 2011; 104:590-598.
65. Javadi B, Sahebkar A, Emami S. A survey on saffron in major islamic traditional medicine books. Iran J Basic Med Sci 2013; 16:1-11.
66. Modaghegh MH, Shahabian M, Esmaeili HA, Rajbai O, Hosseinzadeh H. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008; 15:1032-1037.
67. Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res 2010; 24:990-994.
68. Boskabady MH, Shafei MN, Shakiba A, Sefidi HS. Effect of aqueous-ethanol extract from Crocus sativus (saffron) on guinea-pig isolated heart. Phytother Res 2008; 22:330-334.
69. Fabrazzo M, Monteleone P, Prisco V, Perris F, Catapano F, Tortorella A, et al. Olanzapine is faster than haloperidol in inducing metabolic abnormalities in schizophrenic and bipolar patients. Neuropsychobiology 2015; 72:29-36.
Iranian Journal of Basic Medical Sciences
Volume 22, Issue 12
December 2019
Pages 1476-1482

Files

Share

How to cite

Statistics