Biochemical pathways triggered by antipsychotics in human oligodendrocytes: potential of discovering new treatment targets

Schizophrenia is a psychiatric disorder that affects more than 21 million people worldwide. It is an incurable disorder and the primary means of managing symptoms is through administration of pharmacological treatments, which consist heavily of antipsychotics. First-generation antipsychotics have the properties of D-2 receptor antagonists. Second-generation antipsychotics are antagonists of both D-2 and 5HT(2) receptors. Recently, there has been increasing interest in the effects of antipsychotics beyond their neuronal targets and oligodendrocytes are one of the main candidates. Thus, our aim was to evaluate the molecular effects of typical and atypical drugs across the proteome of the human oligodendrocyte cell line, MO3.13. For this, we performed a mass spectrometry-based, bottom-up shotgun proteomic analysis to identify differences triggered by typical (chlorpromazine and haloperidol) and atypical (quetiapine and risperidone) antipsychotics. Proteins which showed changes in their expression levels were analyzed in silico using Ingenuity (R) Pathway Analysis, which implicated dysregulation of canonical pathways for each treatment. Our results shed light on the biochemical pathways involved in the mechanisms of action of these drugs, which may guide the identification of novel biomarkers and the development of new and improved treatments10CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP460289/2014-42015/23049-0; 2017/18242-1; 2014/14881-1; 2014/10068-4; 2017/25588-1; 2018/03673-1CB-T, VdA, JC, and DM-d-S were supported by FAPESP (São Paulo Research Foundation), grants 2015/23049-0, 2017/18242-1, 2014/14881-1, 2014/10068-4, 2017/25588-1, and 2018/03673-1. DM-d-S was also supported by The Brazilian National Council for Scientific and Technological Development (CNPq), grant 460289/2014-4 and Serrapilheira Institute, grant number Serra-1709-1634