School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; Centre for Biodiscovery Wellington, Victoria University of Wellington, Wellington, New Zealand.
Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Cell Signal. 2022 Nov;99:110449. doi: 10.1016/j.cellsig.2022.110449. Epub 2022 Aug 27.
Multiple sclerosis is a disease characterised by demyelination of axons in the central nervous system. The atypical antipsychotic drug clozapine has been shown to attenuate disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model that is useful for the study of multiple sclerosis. However, the mechanism of action by which clozapine reduces disease in EAE is poorly understood. To better understand how clozapine exerts its protective effects, we investigated the underlying signalling pathways by which clozapine may reduce immune cell migration by evaluating chemokine and dopamine receptor-associated signalling pathways. We found that clozapine inhibits migration of immune cells by reducing chemokine production in microglia cells by targeting NF-κB phosphorylation and promoting an anti-inflammatory milieu. Furthermore, clozapine directly targets immune cell migration by changing Ca levels within immune cells and reduces the phosphorylation of signalling protein AKT. Linking these pathways to the antagonising effect of clozapine on dopamine and serotonin receptors, we provide insight into how clozapine alters immune cells migration by directly targeting the underlying migration-associated pathways.
多发性硬化症是一种以中枢神经系统轴突脱髓鞘为特征的疾病。非典型抗精神病药氯氮平已被证明可减轻实验性自身免疫性脑脊髓炎（EAE）的疾病严重程度，EAE 是一种用于多发性硬化症研究的有用的小鼠模型。然而，氯氮平降低 EAE 疾病的作用机制尚不清楚。为了更好地了解氯氮平如何发挥其保护作用，我们研究了氯氮平可能通过评估趋化因子和多巴胺受体相关信号通路来减少免疫细胞迁移的潜在信号通路。我们发现，氯氮平通过靶向 NF-κB 磷酸化和促进抗炎微环境来减少小胶质细胞中趋化因子的产生，从而抑制免疫细胞的迁移。此外，氯氮平通过改变免疫细胞内的 Ca 水平直接靶向免疫细胞迁移，并减少信号蛋白 AKT 的磷酸化。将这些通路与氯氮平对多巴胺和 5-羟色胺受体的拮抗作用联系起来，我们深入了解了氯氮平如何通过直接靶向潜在的迁移相关通路来改变免疫细胞的迁移。
