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

[This corrects the article DOI: 10.3389/fnmol.2021.673144.].

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

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.

Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia.

Oligodendrocytes are the glial cells responsible for the formation of the myelin sheath around axons. During neurodevelopment, oligodendrocytes undergo maturation and differentiation, and later remyelination in adulthood. Abnormalities in these processes have been associated with behavioral and cognitive dysfunctions and the development of various mental illnesses like schizophrenia. Several studies have implicated oligodendrocyte dysfunction and myelin abnormalities in the disorder, together with altered expression of myelin-related genes such as Olig2, CNP, and NRG1. However, the molecular mechanisms subjacent of these alterations remain elusive. Schizophrenia is a severe, chronic psychiatric disorder affecting more than 23 million individuals worldwide and its symptoms usually appear at the beginning of adulthood. Currently, the major therapeutic strategy for schizophrenia relies on the use of antipsychotics. Despite their widespread use, the effects of antipsychotics on glial cells, especially oligodendrocytes, remain unclear. Thus, in this review we highlight the current knowledge regarding oligodendrocyte dysfunction in schizophrenia, compiling data from (epi)genetic studies and up-to-date models to investigate the role of oligodendrocytes in the disorder. In addition, we examined potential targets currently investigated for the improvement of schizophrenia symptoms. Research in this area has been investigating potential beneficial compounds, including the D-amino acids D-aspartate and D-serine, that act as NMDA receptor agonists, modulating the glutamatergic signaling; the antioxidant N-acetylcysteine, a precursor in the synthesis of glutathione, protecting against the redox imbalance; as well as lithium, an inhibitor of glycogen synthase kinase 3ß (GSK3ß) signaling, contributing to oligodendrocyte survival and functioning. In conclusion, there is strong evidence linking oligodendrocyte dysfunction to the development of schizophrenia. Hence, a better understanding of oligodendrocyte differentiation, as well as the effects of antipsychotic medication in these cells, could have potential implications for understanding the development of schizophrenia and finding new targets for drug development.