Intra-Cellular Therapies, Inc., Alexandria Center for Life Sciences, New York, New York 10016
Intra-Cellular Therapies, Inc., Alexandria Center for Life Sciences, New York, New York 10016.
J Neurosci. 2023 Feb 1;43(5):863-877. doi: 10.1523/JNEUROSCI.0984-22.2022. Epub 2022 Dec 22.
Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder (www.ClinicalTrials.gov). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood-brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges. Lumateperone is indicated in adults to treat schizophrenia and depressive episodes associated with bipolar I or II disorder, as monotherapy and adjunctive therapy with lithium or valproate. Because aberrant immune system activity is associated with increased depressive symptoms, the relationship between lumateperone and immune function was studied. Here, lumateperone reduced the levels of proinflammatory cytokines that were increased following an immune challenge or stress in mice. Additionally, lumateperone altered genes and pathways that maintain blood-brain barrier integrity, restored an index of blood-brain barrier function, reduced anxiety-like behavior in rodents, and enhanced mammalian target of rapamycin complex 1 pathway signaling in the PFC. These results highlight the anti-inflammatory actions of lumateperone and describe how lumateperone may reduce immune pathophysiology, which is associated with depressive symptoms.
鲁马西酮适用于成人精神分裂症的治疗，以及成人单相或双相 I 或 II 型障碍（双相抑郁）相关的抑郁发作的治疗，可作为单药治疗，也可与锂或丙戊酸盐联合治疗（Calabrese 等人，2021 年）。目前，它正在接受治疗重度抑郁症的评估（www.ClinicalTrials.gov）。鲁马西酮通过选择性调节大脑中的 5-羟色胺、多巴胺和谷氨酸神经递质的传递而起作用。然而，其他机制也可能参与鲁马西酮的作用，并且由于免疫系统和精神健康之间的联系，我们假设鲁马西酮可能通过使病理性炎症正常化来改善抑郁症状，至少部分如此。在这里，我们表明，在接受急性免疫挑战的雄性和雌性 C57BL/6 小鼠中，鲁马西酮降低了大脑和血清中异常升高的关键促炎细胞因子（例如，IL-1β、IL-6 和 TNF-α）的水平；鲁马西酮还降低了急性行为应激下雄性小鼠的促炎细胞因子。此外，我们证明鲁马西酮改变了参与维持组织完整性和支持血脑屏障功能的关键基因/途径，如 Claudin-5 和细胞间黏附分子 1。此外，在急性应激的雄性 Sprague Dawley 大鼠中，鲁马西酮表现出抗焦虑和抗快感缺失样特性，同时增强了前额叶皮质中雷帕霉素靶蛋白复合物 1 通路的活性。总之，我们的临床前研究结果表明，鲁马西酮除了能够调节多种神经递质系统外，还可以通过减轻急性炎症挑战的影响来发挥作用。鲁马西酮适用于成人治疗精神分裂症和单相或双相 I 或 II 型障碍相关的抑郁发作，作为单药治疗和锂或丙戊酸盐的辅助治疗。由于异常的免疫系统活动与增加的抑郁症状有关，因此研究了鲁马西酮与免疫功能之间的关系。在这里，鲁马西酮降低了在免疫挑战或应激后升高的促炎细胞因子的水平。此外，鲁马西酮改变了维持血脑屏障完整性的基因和途径，恢复了血脑屏障功能的一个指标，减少了啮齿动物的焦虑样行为，并增强了前额叶皮质中雷帕霉素靶蛋白复合物 1 通路的信号。这些结果强调了鲁马西酮的抗炎作用，并描述了鲁马西酮如何减轻与抑郁症状相关的免疫病理生理学。
