Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13.

Ana Caroline Brambilla Falvella,Jaime E Hallak,José A Crippa,Bradley Joseph Smith,Valéria De Almeida,Fernanda Crunfli,Licia C Silva-Costa,Antonio W Zuardi,Daniel Martins-De-Souza,Aline G F Valença

doi:10.3389/fnmol.2021.673144

Abstract

Cannabidiol, a compound of Cannabis sativa, has been proposed as an alternative treatment of schizophrenia. Preclinical and clinical data have suggested that cannabidiol shares more similarity with atypical antipsychotics than typical, both of which are customarily used to manage schizophrenia symptoms. While oligodendrocytes are known to be relevant targets of antipsychotics, the biochemical knowledge in this regard is still limited. Here we evaluated the molecular pathways modulated by cannabidiol compared to the antipsychotics clozapine (atypical) and haloperidol (typical), additionally evaluating the effects of benztropine, a muscarinic receptor antagonist that displays a protective effect in oligodendrocytes and myelination. For this purpose, we employed nano-chromatography coupled with mass spectrometry to investigate the proteomic response to these drugs both in healthy oligodendrocytic cells and in a cuprizone-based toxicity model, using the human oligodendrocyte precursor cell line MO3.13. Cannabidiol shares similarities of biochemical pathways with clozapine and benztropine, in agreement with other studies that indicated an atypical antipsychotic profile. All drugs tested affected metabolic and gene expression pathways and cannabidiol, benztropine, and clozapine modulated cell proliferation and apoptosis when administered after cuprizone-induced toxicity. These general pathways are associated with cuprizone-induced cytotoxicity in MO3.13 cells, indicating a possible proteomic approach when acting against the toxic effects of cuprizone. In conclusion, although modeling oligodendrocytic cytotoxicity with cuprizone does not represent the entirety of the pathophysiology of oligodendrocyte impairments, these results provide insight into the mechanisms associated with the effects of cannabidiol and antipsychotics against cuprizone toxicity, offering new directions of study for myelin-related processes and deficits.

Highlights

Schizophrenia is a severe and chronic mental disorder that affects over 20 million people worldwide
Comparing the effects of cannabidiol and antipsychotics with the putative protective function of benztropine on the MO3.13 proteome, we found that all drugs modulated proteins related to metabolism, antioxidant system, and RNA splicing
We found changes in the constituent proteins of several molecular mechanisms and biological processes in oligodendrocytic cells resulting from benztropine administration, which might be associated with its ability to induce myelination and oligodendrocyte progenitor cells (OPCs) differentiation

Summary

Introduction

Schizophrenia is a severe and chronic mental disorder that affects over 20 million people worldwide It is characterized by positive, negative, and cognitive symptoms (Azorin et al, 2014; Owen et al, 2016) which are primarily treated with antipsychotics. OLs are cells present in brain white matter and are responsible for axon myelination, and dysfunction of this process has been implicated in neuronal dysconnectivity (Cassoli et al, 2015; Jørgensen et al, 2016; Vikhreva et al, 2016) This dysconnectivity and abnormalities in white matter have been implicated in the pathophysiology of schizophrenia (Bernard et al, 2015; Orban et al, 2017; Saito et al, 2018). The biology of OPCs and mature OLs is an essential focal point to understand the role of these cells in the pathophysiology of—and the development of new treatment for—schizophrenia (de Almeida and Martins-deSouza, 2018)

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Results

Conclusion