用于治疗精神分裂症和双相情感障碍的最佳抗精神病药物之一是奥氮平(OLA)。然而,由于肝脏损害等不利的不良反应,其使用受到限制,血脂异常,和体重增加。本研究的主要目的是检查OLA产生的代谢破坏的信号传导机制。此外,还观察了萝卜硫烷(SFN)和β-谷甾醇(βSS)对OLA引起的肥胖和代谢毒性的潜在保护作用。共树立五组雄性Wistar年夜鼠,包括控制,OLA,SFN+OLA,βSS+OLA,和组合+OLA组。肝脏组织病理学,生化分析,最终的身体重量,肝功能,氧化应激,和促炎细胞因子进行评估。除了FOXO的相对表达,PI3K/AKT的信号通路,还评估了JAK/STAT3和MAPK。SFN和/或βSS缓解了OLA引起的所有生化和肝组织病理学异常。收缩压(SBP)大幅下降,促炎细胞因子,血清脂质轮廓参数,肝MDA,TBIL,AST,ALT通过SFN或/和βSS降低。总而言之,OLA的有害作用由Akt/FOXO3a/ATG12,Ras/SOS2/Raf-1/MEK/ERK1/2和Smad3,4/TGF-β信号通路的改变介导.SFN和/或βSS的管理有可能减轻代谢缺陷,生化失衡,肝脏组织学异常,以及OLA通过调节上述信号通路诱导的总体不利后果。
One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of
sulforaphane (SFN) and β-sitosterol (βSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, βSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or βSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and βSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-β signaling pathways. The administration of SFN and/or βSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways.