Shagdarova Balzhima, Melnikova Viktoria, Kostenko Valentina, Konovalova Mariya, Zhuikov Vsevolod, Varlamov Valery, Svirshchevskaya Elena
Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia.
Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia.
Biomedicines. 2024 Oct 16;12(10):2358. doi: 10.3390/biomedicines12102358.
The issue of human mental health is gaining more and more attention nowadays. However, most mental disorders are treated with antipsychotic drugs that cause weight gain and metabolic disorders, which include olanzapine (OLZ). The search for and development of natural compounds for the prevention of obesity when taking antipsychotic drugs is an urgent task. The biopolymer chitosan (Chi) and its derivatives have lipid-lowering and anti-diabetic properties, which makes them potential therapeutic substances for use in the treatment of metabolic disorders. The purpose of this work was to analyze the effect of the natural biopolymer Chi, its derivative -succinyl chitosan (SuChi), and Orlistat (ORL) as a control on the effects caused by the intake of OLZ in a mouse model.
Mice were fed with pearl barley porridge mixed with OLZ or combinations OLZ + Chi, OLZ + SuChi, or OLZ + ORL for 2 months. The weight, lipid profile, blood chemokines, expression of genes associated with appetite regulation, and behavior of the mice were analyzed in dynamics.
For the first time, data were obtained on the effects of Chi and SuChi on metabolic changes during the co-administration of antipsychotics. Oral OLZ increased body weight, food and water intake, and glucose, triglyceride, and cholesterol levels in blood. ORL and SuChi better normalized lipid metabolism than Chi, decreasing triglyceride and cholesterol levels. OLZ decreased the production of all chemokines tested at the 4th week of treatment and increased CXCL1, CXCL13, and CCL22 chemokine levels at the 7th week. All of the supplements corrected the level of CXCL1, CXCL13, and CCL22 chemokines but did not recover suppressed chemokines. SuChi and ORL stimulated the expression of satiety associated proopiomelanocortin (POMC) and suppressed the appetite-stimulating Agouti-related protein (AgRP) genes. All supplements improved the locomotion of mice.
Taken collectively, we found that SuChi more than Chi possessed an activity close to that of ORL, preventing metabolic disorders in mice fed with OLZ. As OLZ carries positive charge and SuChi is negatively charged, we hypothesized that SuChi's protective effect can be explained by electrostatic interaction between OLZ byproducts and SuChi in the gastrointestinal tract.
如今，人类心理健康问题越来越受到关注。然而，大多数精神障碍是用会导致体重增加和代谢紊乱的抗精神病药物治疗的，其中包括奥氮平（OLZ）。寻找和开发用于预防服用抗精神病药物时肥胖的天然化合物是一项紧迫任务。生物聚合物壳聚糖（Chi）及其衍生物具有降血脂和抗糖尿病特性，这使其成为治疗代谢紊乱的潜在治疗物质。这项工作的目的是分析天然生物聚合物Chi、其衍生物琥珀酰壳聚糖（SuChi）以及作为对照的奥利司他（ORL）对小鼠模型中摄入OLZ所引起的影响。
给小鼠喂食与OLZ混合的珍珠大麦粥或OLZ + Chi、OLZ + SuChi或OLZ + ORL的组合，持续2个月。动态分析小鼠的体重、血脂谱、血液趋化因子、与食欲调节相关基因的表达以及行为。
首次获得了关于Chi和SuChi在联合使用抗精神病药物期间对代谢变化影响的数据。口服OLZ会增加体重、食物和水的摄入量以及血液中的葡萄糖、甘油三酯和胆固醇水平。与Chi相比，ORL和SuChi能更好地使脂质代谢正常化，降低甘油三酯和胆固醇水平。在治疗第4周时，OLZ降低了所有测试趋化因子的产生，而在第7周时增加了CXCL1、CXCL13和CCL22趋化因子水平。所有补充剂都纠正了CXCL1、CXCL13和CCL22趋化因子的水平，但未恢复被抑制的趋化因子。SuChi和ORL刺激了与饱腹感相关的阿黑皮素原（POMC）的表达，并抑制了刺激食欲的刺鼠相关蛋白（AgRP）基因。所有补充剂都改善了小鼠的运动能力。
总体而言，我们发现SuChi比Chi具有更接近ORL的活性，可预防喂食OLZ的小鼠出现代谢紊乱。由于OLZ带正电荷而SuChi带负电荷，我们推测SuChi的保护作用可以通过胃肠道中OLZ副产物与SuChi之间的静电相互作用来解释。
