Carnosic acid prevented olanzapine-induced metabolic disorders through AMPK activation
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ORIGINAL ARTICLE
Carnosic acid prevented olanzapine-induced metabolic disorders through AMPK activation Bibi Marjan Razavi1,2 · Amir Reza Abazari2 · Maryam Rameshrad3 · Hossein Hosseinzadeh2,4 Received: 20 June 2020 / Revised: 1 September 2020 / Accepted: 7 September 2020 © Springer Nature B.V. 2020
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. Keywords Olanzapine · Metabolic syndrome · Obesity · Carnosic acid · Rosemary · AMPK
Introduction Nowadays, overweight and obesity are considered a rapidly developing threat to global health. They are classified as the main risk factors for, hypertension, stroke, coronary heart
* Hossein Hosseinzadeh [email protected] 1
Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
2
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
3
Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
4
Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
disease, non-insulin-dependent (type II) diabetes, and various types of cancers [1]. Atypical antipsychotics are considered as the first-line therapy for acute and long term treatment of schizophrenia [2]. According to several documents, many of the atypical antipsychotic med
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