Kemotech Srl, Edificio 3, Località Piscinamanna, 09010 Pula, CA, Italy.
Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy.
Eur Neuropsychopharmacol. 2017 Jul;27(7):667-678. doi: 10.1016/j.euroneuro.2017.03.010. Epub 2017 Apr 2.
Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.
体重增加是大多数非典型抗精神病药物（如奥氮平）的一个重要副作用。此外，尽管已经明确了许多具有代谢副作用的动物模型，但还需要考虑与其他途径的相互作用。内源性大麻素系统和 CB1 受体（CB1R）是参与体重和能量平衡的最有前途的中枢和外周靶点之一。在这项研究中，我们开发了一种基于大鼠的模型，该模型经过 15 天的奥氮平治疗后会出现体重增加和与能量平衡和葡萄糖代谢调节相关的血液参数改变。因此，我们分析了新型 CB1R 中性拮抗剂 NESS06SM 是否以及通过何种机制可以减轻奥氮平的不良代谢作用，与参考 CB1R 反向激动剂利莫那班相比。我们的结果显示，奥氮平治疗的雌性大鼠伏隔核中的大麻素标志物和下丘脑中的食欲刺激/食欲抑制标志物发生了改变。这些分子修饰可以解释过量的食物摄入和由此产生的体重增加。此外，我们证实，CB1R 拮抗剂/反向激动剂化合物的共同治疗可减少食物摄入和体重增加，并恢复所有血液参数，而不会改变奥氮平对行为的积极影响。此外，利莫那班和 NESS06SM 恢复了奥氮平改变的肝脏和脂肪组织中的代谢酶。因此，CB1 受体拮抗剂/反向激动剂化合物可能是治疗奥氮平引起的体重增加的候选药物。
