Chestnykh Daria, Mühle Christiane, Schumacher Fabian, Kalinichenko Liubov S, Löber Stefan, Gmeiner Peter, Alzheimer Christian, von Hörsten Stephan, Kleuser Burkhard, Uebe Steffen, Ekici Arif B, Gulbins Erich, Kornhuber Johannes, Jin Hee Kyung, Bae Jae-Sung, Lourdusamy Anbarasu, Müller Christian P
Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
Mol Psychiatry. 2025 Jan 17. doi: 10.1038/s41380-025-02893-6.
Schizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD's work only in a limited number of patients and may have cognition impairing side effects. A growing body of evidence points out the potential involvement of abnormal sphingolipid metabolism in the pathophysiology of schizophrenia. Here, an analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of SMPD1 and SMPD3 genes coding for acid- (ASM) and neutral sphingomyelinase-2 (NSM). In a rat model of psychosis using amphetamine hypersensitization, we found a locally restricted increase of ASM activity in the prefrontal cortex (PFC). Short-term haloperidol (HAL) treatment reversed behavioral symptoms and the ASM activity. A sphingolipidomic analysis confirmed an altered ceramide metabolism in the PFC during psychosis. Targeting enhanced ASM activity in a psychotic-like state with the ASM inhibitor KARI201 reversed psychotic like behavior and associated changes in the sphingolipidome. While effective HAL treatment led to locomotor decline and cognitive impairments, KARI201 did not. An RNA sequencing analysis of the PFC suggested a dysregulation of numerous schizophrenia related genes including Olig1, Fgfr1, Gpr17, Gna12, Abca2, Sox1, Dpm2, and Rab2a in the rat model of psychosis. HAL and KARI201 antipsychotic effects were associated with targeting expression of other schizophrenia associated genes like Col6a3, Slc22a8, and Bmal1, or Nr2f6a, respectively, but none affecting expression of sphingolipid regulating genes. Our data provide new insight into a potentially pathogenic mechanism of schizophrenia and suggest a new pharmaco-treatment strategy with reduced side effects.
精神分裂症是一种慢性严重精神障碍。目前使用抗精神病药物（APD）进行治疗。然而，APD仅对少数患者有效，且可能有认知损害的副作用。越来越多的证据指出，异常的鞘脂代谢可能参与精神分裂症的病理生理学过程。在此，对精神分裂症患者的人类基因多态性和脑基因表达进行分析，确定了编码酸性鞘磷脂酶（ASM）和中性鞘磷脂酶-2（NSM）的SMPD1和SMPD3基因之间的关联。在使用苯丙胺超敏反应建立的精神病大鼠模型中，我们发现前额叶皮质（PFC）中ASM活性局部受限升高。短期氟哌啶醇（HAL）治疗可逆转行为症状和ASM活性。鞘脂组学分析证实精神病发作期间PFC中的神经酰胺代谢发生改变。用ASM抑制剂KARI201靶向治疗类精神病状态下增强的ASM活性，可逆转类精神病行为及鞘脂组的相关变化。虽然有效的HAL治疗导致运动能力下降和认知障碍，但KARI201没有。对PFC的RNA测序分析表明，在精神病大鼠模型中，包括Olig1、Fgfr1、Gpr17、Gna12、Abca2、Sox1、Dpm2和Rab2a在内的许多与精神分裂症相关的基因失调。HAL和KARI201的抗精神病作用分别与靶向其他精神分裂症相关基因如Col6a3、Slc22a8和Bmal1或Nr2f6a的表达有关，但均不影响鞘脂调节基因的表达。我们的数据为精神分裂症潜在的致病机制提供了新见解，并提出了一种副作用较小的新药物治疗策略。
