Bove Maria, Lama Adriano, Schiavone Stefania, Pirozzi Claudio, Tucci Paolo, Sikora Vladyslav, Trinchese Giovanna, Corso Gaetano, Morgese Maria Grazia, Trabace Luigia
Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, Foggia 71122, Italy.
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, Naples 80131, Italy.
Biomed Pharmacother. 2022 May;149:112820. doi: 10.1016/j.biopha.2022.112820. Epub 2022 Mar 12.
Drug-naïve psychotic patients show metabolic and hepatic dysfunctions. The rat social isolation model of psychosis allows to investigate mechanisms leading to these disturbances to which oxidative stress crucially contributes. Here, we investigated isolation-induced central and peripheral dysfunctions in glucose homeostasis and insulin sensitivity, along with redox dysregulation. Social isolation did not affect basal glycemic levels and the response to glucose and insulin loads in the glucose and insulin tolerance tests. However, HOMA-Index value were increased in isolated (ISO) rats. A hypothalamic reduction of AKT phosphorylation and a trend toward an increase in AMPK phosphorylation were observed following social isolation, accompanied by reduced GLUT-4 levels. Social isolation also induced a reduction of phosphorylation of the insulin receptor, of AKT and GLUT-2, and a decreased phosphorylation of AMPK in the liver. Furthermore, a significant reduction in hepatic CPT1 and PPAR-α levels was detected. ISO rats also showed significant elevations in hepatic ROS amount, lipid peroxidation and NOX4 expression, whereas no differences were detected in NOX2 and NOX1 levels. Expression of SOD2 in the mitochondrial fraction and SOD1 in the cytosolic fraction was not altered following social isolation, whereas SOD activity was increased. Furthermore, a decrease of hepatic CAT and GSH amount was observed in ISO rats compared to GRP animals. Our data suggest that the increased oxidant status and antioxidant capacity modifications may trigger hepatic and systemic insulin resistance, by altering signal hormone pathway and sustaining subsequent alteration of glucose homeostasis and metabolic impairment observed in the social isolation model of psychosis.
未服用过药物的精神病患者存在代谢和肝功能障碍。精神病的大鼠社会隔离模型有助于研究导致这些紊乱的机制，氧化应激在其中起着关键作用。在此，我们研究了隔离诱导的葡萄糖稳态和胰岛素敏感性的中枢和外周功能障碍，以及氧化还原失调。社会隔离在葡萄糖和胰岛素耐量试验中不影响基础血糖水平以及对葡萄糖和胰岛素负荷的反应。然而，隔离（ISO）大鼠的HOMA-指数值升高。社会隔离后观察到下丘脑AKT磷酸化降低以及AMPK磷酸化有增加趋势，同时伴有GLUT-4水平降低。社会隔离还导致肝脏中胰岛素受体、AKT和GLUT-2的磷酸化减少，以及AMPK磷酸化降低。此外，检测到肝脏CPT1和PPAR-α水平显著降低。ISO大鼠肝脏中的ROS量、脂质过氧化和NOX4表达也显著升高，而NOX2和NOX1水平未检测到差异。社会隔离后线粒体部分的SOD2和胞质部分的SOD1表达未改变，而SOD活性增加。此外，与对照组动物相比，ISO大鼠肝脏中的CAT和GSH量减少。我们的数据表明，氧化状态增加和抗氧化能力改变可能通过改变信号激素途径并维持精神病社会隔离模型中观察到的葡萄糖稳态和代谢损害的后续改变，从而引发肝脏和全身胰岛素抵抗。
