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Carnosic acid prevented olanzapine-induced metabolic disorders through AMPK activation

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Abstract

Olanzapine, an atypical antipsychotic medication, has been associated with weight gain and metabolic toxicity, especially in long term usage. Carnosic acid (CA), a major constituent of rosemary extract, has been shown to improve metabolic abnormalities. In this experiment, the effect of CA on olanzapine-induced obesity and metabolic toxicity has been evaluated. Female Wistar rats were divided into six groups. (1) control; (2) olanzapine (5 mg/kg/day, IP); (3, 4 and 5) olanzapine (5 mg/kg/day, IP) plus CA (5, 10 and 20 mg/kg/day, gavage) and (6) CA (20 mg/kg/day, gavage). Bodyweight and food intake were measured during the study. After 14 days, mean systolic blood pressure (MSBP), glycemia, serum lipid profile, the serum concentration of leptin, insulin, AMPK, P-AMPK, and P-ACC liver protein levels were evaluated. The mean weight in the group received olanzapine increased by 4.8 g at the end of the study. The average food intake was increased by olanzapine. Olanzapine increased triglyceride, fasting blood glucose (FBG), and leptin levels. It increased MSBP and down-regulated P-AMPK/AMPK ratio and P-ACC protein levels. CA (three doses) decreased body weight gain and reduced average food intake at 10 and 20 mg/kg. CA especially at the highest dose decreased the changes in lipid profile, FBG, leptin level, and MSBP. P-AMPK/AMPK and P-ACC protein levels were increased by carnosic acid. In conclusion, the activation of AMPK by CA can be proposed as a key mechanism against olanzapine-induced metabolic toxicity where the activation of AMPK increases fat consumption and regulates glucose hemostasis in the liver.

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References

  1. WHO (2000) Obesity: preventing and managing the global epidemic Report of a WHO Consultation (WHO Technical Report Series 894)

  2. Lysaker PH, Pattison ML, Leonhardt BL et al (2018) Insight in schizophrenia spectrum disorders: relationship with behavior, mood and perceived quality of life, underlying causes and emerging treatments. World Psychiatr 17:12–23

    Google Scholar 

  3. Corfitsen HT, Krantz B, Larsen A et al (2020) Molecular pathway analysis associates alterations in obesity-related genes and antipsychotic-induced weight gain. Acta Neuropsychiatr 32:72–83

    PubMed  Google Scholar 

  4. Allison D, Mentore J, Heo M et al (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696

    CAS  PubMed  Google Scholar 

  5. Patil BM, Kulkarni NM, Unger BS (2006) Elevation of systolic blood pressure in an animal model of olanzapine induced weight gain. Eur J Pharmacol 551:112–115

    CAS  PubMed  Google Scholar 

  6. Kirk S, Glazebrook J, Grayson B et al (2009) Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology 207:119–125

    CAS  PubMed  Google Scholar 

  7. Gunes A, Melkersson K, Scordo M et al (2009) Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol 29:65–68

    CAS  PubMed  Google Scholar 

  8. Evers SS, Calcagnoli F, Dijk V et al (2010) Olanzapine causes hypothermia inactivity, a deranged feeding pattern and weight gain in female Wistar rats. Pharmacol Biochem Behav 97:163–169

    CAS  PubMed  Google Scholar 

  9. Weston-Greena K, Huanga X et al (2011) Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats. Behav Brain Res 217:337–346

    Google Scholar 

  10. de Macedo LM, Dos Santos EM, Militao L et al (2020) Rosemary (Rosmarinus officinalis L., syn salvia rosmarinus spenn.) and its topical applications: a review. Plants 9:651

    PubMed Central  Google Scholar 

  11. Wang T, Takikawa Y, Satoh T et al (2011) Carnosic acid prevents obesity and hepatic steatosis in ob/ob mice. Hepatol Res 41:87–92

    CAS  PubMed  Google Scholar 

  12. Zhao Y, Sedighi R, Wang P et al (2015) Carnosic acid as a major bioactive component in rosemary extract ameliorates high-fat-diet-induced obesity and metabolic syndrome in mice. J Agric Food Chem 63:4843–4852

    CAS  PubMed  Google Scholar 

  13. Romo-Vaquero M, Larrosa M, Yanez-Gascon MJ et al (2014) A rosemary extract enriched in carnosic acid improves circulating adipocytokines and modulates key metabolic sensors in lean Zucker rats: critical and contrasting differences in the obese genotype. Mol Nutr Food Res 58:942–953

    CAS  PubMed  Google Scholar 

  14. Park MY, Sung MK (2015) Carnosic acid attenuates obesity-induced glucose intolerance and hepatic fat accumulation by modulating genes of lipid metabolism in C57BL/6J-ob/ob mice. J Sci Food Agric 95:828–835

    CAS  PubMed  Google Scholar 

  15. Razavi BM, Hosseinzadeh H (2014) A review of the effects of Nigella sativa L. and its constituent, thymoquinone, in metabolic syndrome. J Endocrinol Invest 37:1031–1040

    CAS  PubMed  Google Scholar 

  16. Razavi BM, Lookian F, Hosseinzadeh H (2017) Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats. Biomed Pharmacother 92:726–731

    CAS  PubMed  Google Scholar 

  17. Hosseini A, Hosseinzadeh H (2015) A review on the effects of Allium sativum (Garlic) in metabolic syndrome. J Endocrinol Invest 38(11):1147–1157

    CAS  PubMed  Google Scholar 

  18. Tabeshpour J, Razavi BM, Hosseinzadeh H (2017) Effects of Avocado (Persea americana) on metabolic syndrome: a comprehensive systematic review. Phytother Res 31:819–837

    PubMed  Google Scholar 

  19. Hassani FV, Shirani K, Hosseinzadeh H (2016) Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review. Naunyn-Schmiedeberg's Arch Pharmacol 389:931–949

    CAS  Google Scholar 

  20. Razavi BM, Hosseinzadeh H (2017) Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric 97:1679–1685

    CAS  PubMed  Google Scholar 

  21. Mollazadeh H, Hosseinzadeh H (2016) Cinnamon effects on metabolic syndrome: a review based on its mechanisms. Iran J Basic Med Sci 19(12):1258–1270

    PubMed  PubMed Central  Google Scholar 

  22. Akaberi M, Hosseinzadeh H (2016) Grapes (Vitis vinifera) as a potential candidate for the therapy of the metabolic syndrome. Phytother Res 30:540–56

    CAS  PubMed  Google Scholar 

  23. Hosseinzadeh H, Nassiri-Asl M (2014) Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Invest 37:783–788

    CAS  PubMed  Google Scholar 

  24. Ruderman NB, Carling D, Prentki M et al (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123:2764–2772

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ninomiya K, Matsuda H, Shimoda H et al (2004) Carnosic acid, a new class of lipid absorption inhibitor from sage. Bioorg Med Chem lett 14:1943–1946

    CAS  PubMed  Google Scholar 

  26. Lorenz JN (2002) A practical guide to evaluating cardiovascular, renal, and pulmonary function in mice. Am J Physiol Regul Integr Comp Physiol 282:R1565–R1582

    CAS  PubMed  Google Scholar 

  27. Arjona AA, Zhang SX, Adamson B et al (2004) An animal model of antipsychotic-induced weight gain. Behav Brain Res 152:121–127

    CAS  PubMed  Google Scholar 

  28. Barton BB, Segger F, Fischer K et al (2020) Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf 19:295–314

    CAS  PubMed  Google Scholar 

  29. Malekzadeh S, Heidari MR, Razavi BM et al (2019) Effect of safranal, a constituent of saffron, on olanzapine (an atypical antipsychotic) induced metabolic disorders in rat. Iran J Basic Med Sci 22:1476–1482

    PubMed  PubMed Central  Google Scholar 

  30. Goudie AJ, Smith JA, Halford JC (2002) Characterization of olanzapine-induced weight gain in rats. J Psychopharmacol 16:291–296

    CAS  PubMed  Google Scholar 

  31. Nielsen MO, Rostrup E, Wulff S et al (2016) Striatal reward activity and antipsychotic-associated weight change in patients with schizophrenia undergoing initial treatment. JAMA Psychiatry 73:121–128

    PubMed  Google Scholar 

  32. Lord CC, Wyler SC, Wan R et al (2017) The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest 127:3402–3406

    PubMed  PubMed Central  Google Scholar 

  33. Deng C, Weston-Green K, Huang XF (2010) The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog Neuro-psychopharmacol biol Psychiatry 34:1–4

    Google Scholar 

  34. Ferno J, Varela L, Skrede S et al (2011) Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. PLoS ONE 6:e20571

    PubMed  PubMed Central  Google Scholar 

  35. Baeza I, Vigo L, de la Serna E et al (2017) The effects of antipsychotics on weight gain, weight-related hormones and homocysteine in children and adolescents: a 1-year follow-up study. Eur child Adoles Psychiatry 26:35–46

    Google Scholar 

  36. Ailhaud G (2006) Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. Comptes Rendus Biol 329:570–577

    CAS  Google Scholar 

  37. Coccurello R, Moles A (2010) Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design. Pharmacol Ther 127:210–251

    CAS  PubMed  Google Scholar 

  38. Rickels MR, Perez EM, Peleckis AJ et al (2018) Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia. Am J Physiol Endocrinol Met 315:E250–E257

    CAS  Google Scholar 

  39. Minet-Ringuet J, Even PC, Goubern M et al (2006) Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration. Appetite 46:254–262

    CAS  PubMed  Google Scholar 

  40. Monteleone P, Fabrazzo M, Tortorella A et al (2002) Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol 22:424–426

    CAS  PubMed  Google Scholar 

  41. Ader M, Kim SP, Catalano KJ et al (2005) Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes 54:862

    CAS  PubMed  Google Scholar 

  42. Perez-Iglesias R, Crespo-Facorro B, Amado JA et al (2007) 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 68:1733–1740

    PubMed  Google Scholar 

  43. Hosojima H, Togo T, Odawara T et al (2006) Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 20:75–79

    CAS  PubMed  Google Scholar 

  44. Ibarra A, Cases J, Roller M et al (2011) Carnosic acid-rich rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and improves cholesterol levels and glycaemia in mice on a high-fat diet. Br J Nutr 106:1182–1189

    CAS  PubMed  Google Scholar 

  45. Young LH, Li J, Baron SJ et al (2005) AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med 15:110–118

    CAS  PubMed  Google Scholar 

  46. Dyck JRB (2006) AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol 574:95–112

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Huynh MK, Kinyua AW, Yang DJ et al (2016) Hypothalamic AMPK as a regulator of energy homeostasis. Neural Plast. https://doi.org/10.1155/2016/2754078

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hu Y, Young AJ, Ehli EA et al (2014) Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS ONE 9:e93310

    PubMed  PubMed Central  Google Scholar 

  49. Wang T, Takikawa Y, Tabuchi T et al (2012) Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway. J Gastroenterol 47:805–813

    CAS  PubMed  Google Scholar 

  50. Bush ND, Townsend LK, Wright DC (2018) AICAR prevents acute olanzapine-induced disturbances in glucose homeostasis. J Pharmacol Exp Ther 365:526–535

    CAS  PubMed  Google Scholar 

  51. Shamshoum H, Medak KD, Townsend LK et al (2019) AMPK β1 activation suppresses antipsychotic-induced hyperglycemia in mice. FASEB J 33(12):fj.201901820R

    Google Scholar 

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Acknowledgements

The authors are thankful to the National Institute for Medical Research Development (Grant No.:943698) and Mashhad University of Medical Sciences for financial supports. The results described in this paper were part of a student thesis.

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Authors and Affiliations

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

    Bibi Marjan Razavi

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

    Bibi Marjan Razavi, Amir Reza Abazari & Hossein Hosseinzadeh

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

    Maryam Rameshrad

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

    Hossein Hosseinzadeh

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  1. Bibi Marjan Razavi
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  4. Hossein Hosseinzadeh
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Contributions

HH conceived the idea and designed the experiments. ARA performed the experiments and analyzed the data. BMR and MR wrote the manuscript. HH gave all the critical revisions. All authors read and approved the final manuscript.

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Correspondence to Hossein Hosseinzadeh.

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Razavi, B.M., Abazari, A.R., Rameshrad, M. et al. Carnosic acid prevented olanzapine-induced metabolic disorders through AMPK activation. Mol Biol Rep 47, 7583–7592 (2020). https://doi.org/10.1007/s11033-020-05825-5

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