Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Mol Biol Rep. 2020 Oct;47(10):7583-7592. doi: 10.1007/s11033-020-05825-5. Epub 2020 Sep 14.
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.
奥氮平是一种非典型抗精神病药物，与体重增加和代谢毒性有关，尤其是长期使用。迷迭香酸（CA）是迷迭香提取物的主要成分，已被证明可改善代谢异常。在这项实验中，评估了 CA 对奥氮平引起的肥胖和代谢毒性的影响。将雌性 Wistar 大鼠分为六组。（1）对照组；（2）奥氮平（5mg/kg/天，腹腔注射）；（3、4 和 5）奥氮平（5mg/kg/天，腹腔注射）加 CA（5、10 和 20mg/kg/天，灌胃）和（6）CA（20mg/kg/天，灌胃）。在研究期间测量体重和食物摄入量。14 天后，评估平均收缩压（MSBP）、血糖、血清脂质谱、血清瘦素、胰岛素、AMPK、P-AMPK 和 P-ACC 肝蛋白水平。接受奥氮平的组的平均体重在研究结束时增加了 4.8g。奥氮平增加了平均食物摄入量。奥氮平增加了甘油三酯、空腹血糖（FBG）和瘦素水平。它增加了 MSBP 并下调了 P-AMPK/AMPK 比值和 P-ACC 蛋白水平。CA（三剂量）降低了体重增加，并降低了 10 和 20mg/kg 时的平均食物摄入量。CA 尤其是在最高剂量时降低了血脂谱、FBG、瘦素水平和 MSBP 的变化。P-AMPK/AMPK 和 P-ACC 蛋白水平被 CA 激活。总之，CA 对 AMPK 的激活可被认为是对抗奥氮平引起的代谢毒性的关键机制，其中 AMPK 的激活增加脂肪消耗并调节肝脏中的葡萄糖稳态。
