Antipsychotics and cannabidiol effects in cuprizone-treated oligodendrocytes : implications for myelination

Schizophrenia is a psychiatric disorder that affects 20 million people worldwide. Neuronal dysconnectivity can be correlated to symptoms of this disorder, which is related to oligodendrocytes and myelin abnormalities in white matter. In this context, toxic models of demyelination are used to understand the mechanisms involved in these alterations. To achieve this, proteomic approaches are important to understand processes involved in neurological disorders through the elucidation of biochemical bases and identification of differentially expressed pathways and proteins. In this context, we developed an in vitro assay of cuprizone-mediated death in a human oligodendrocyte cell line (MO3.13) to test the effect of benztropine, a molecule that enhances myelination and oligodendrocyte differentiation, and compared its effect with the potential protective effects of antipsychotics (clozapine and haloperidol) and cannabidiol. After the treatments mentioned above, the proteomes were extracted and digested for analysis by nano-chromatography coupled to mass spectrometry to investigate the proteins and pathways affected in oligodendrocytes treated by these drugs. We confirmed that the in vitro model for cuprizone cell death impairs MO3.13 oligodendrocyte viability through disturbances of several biological processes, including energy and lipid metabolism, genetic processes and growth signaling. Furthermore, the administration of antipsychotics, cannabidiol, and benztropine seems to modulate metabolism, genetic factors, cell cycle and cell signaling, which are related to cuprizone-induced cell death, indicating their potential to act against the cuprizone toxic effect. In conclusion, although modeling oligodendrocyte death with cuprizone does not represent the entirety of the pathophysiology of the disorder, these results provide insight into the mechanisms related to antipsychotics¿ and cannabidiol¿s effects against cuprizone toxicity and their implications for developing new pharmaceutical targets and treatment options for schizophrenia (AU)