Studies on Prostaglandin-Endoperoxide Synthase 1: Lower Levels in Schizophrenia and After Treatment with Antipsychotic Drugs in Conjunction with Aspirin

摘要

Background Antipsychotic drugs plus aspirin (acetylsalicylic acid), which targets prostaglandin-endoperoxide synthase 1 (PTGS1: COX1), improved therapeutic outcomes when treating schizophrenia. Our microarray data showed higher levels of PTGS1 mRNA in the dorsolateral prefrontal cortex from subjects with schizophrenia of long duration of illness, suggesting aspirin plus antipsychotic drugs could have therapeutic effects by lowering PTGS1 expression in the cortex of subjects with the disorder. Methods We used Western blotting to measure levels of PTSG1 protein in human postmortem CNS, rat and mouse cortex, and cells in culture. Results Compared with controls, PTGS1 levels were 41% lower in the dorsolateral prefrontal cortex ( P <.01), but not the anterior cingulate or frontal pole, from subjects with schizophrenia. Levels of PTGS1 were not changed in the dorsolateral prefrontal cortex in mood disorders or in the cortex of rats treated with antipsychotic drugs. There was a strong trend ( P= .05) to lower cortical PTGS1 10 months after mice were treated postnatally with polyinosinic–polycytidylic acid sodium salt (Poly I:C), consistent with cortical PTGS1 being lower in adult mice after exposure to an immune activator postnatally. In CCF-STTG1 cells, a human-derived astrocytic cell line, aspirin caused a dose-dependent decrease in PTGS1 that was decreased further with the addition of risperidone. Conclusions Our data suggest low levels of dorsolateral prefrontal cortex PTGS1 could be associated with the pathophysiology of schizophrenia, and improved therapeutic outcome from treating schizophrenia with antipsychotic drugs augmented with aspirin may be because such treatment lowers cortical PTGS1. Schizophrenia , aspirin , COX1 , PTSG1 , postmortem , cortex Significance Statement We showed that levels of PTGS1 messenger RNA were higher in the DLPFC from subjects with schizophrenia of long duration of illness. This was significant, because PTGS1 is targeted by aspirin, which increases the ability of antipsychotic drugs to lessen the symptoms of schizophrenia. Here, we report levels of PTGS1 protein is lower in the DLPFC, but not anterior cingulate or frontal pole, from subjects with schizophrenia and that PTGS1 is not altered in subjects with mood disorders or rats treated with antipsychotic drugs. Levels of PTGS1 were lower in human-derived astrocytes treated with aspirin, an effect augmented by the edition of the antipsychotic drug, risperidone. We propose lower levels of PTGS1 protein in the DLPFC are part of the pathophysiology of schizophrenia, and treatment with aspirin combined with an antipsychotic drug gives improved therapeutic benefits by lowering PTGS1 in subjects with schizophrenia.