Table_1_Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13.XLSX

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.

大麻二酚（Cannabidiol）是大麻（Cannabis sativa）中的一种化合物，此前被提议作为精神分裂症的替代治疗方案。临床前与临床数据表明，相较于典型抗精神病药（typical antipsychotics），大麻二酚与非典型抗精神病药（atypical antipsychotics）的相似性更高，而这两类药物均常用于控制精神分裂症症状。尽管已知少突胶质细胞（oligodendrocytes）是抗精神病药的相关作用靶点，但目前该领域的生化认知仍较为有限。本研究对比评估了大麻二酚与抗精神病药氯氮平（clozapine，非典型）、氟哌啶醇（haloperidol，典型）调控的分子通路，同时评估了苯托品（benztropine）的作用——这是一种毒蕈碱受体拮抗剂（muscarinic receptor antagonist），对少突胶质细胞与髓鞘形成（myelination）具有保护作用。为此，本研究采用纳米液相色谱（nano-chromatography）联用质谱（mass spectrometry）技术，以人类少突胶质前体细胞系MO3.13为模型，探究了上述药物在健康少突胶质细胞以及铜色酮（cuprizone）诱导的毒性模型中引发的蛋白质组学响应。研究发现，大麻二酚的生化通路特征与氯氮平、苯托品具有相似性，这与其他指出大麻二酚具有非典型抗精神病药特性的研究结果一致。所有受试药物均会影响代谢与基因表达通路；在铜色酮诱导毒性后给药时，大麻二酚、苯托品与氯氮平均可调控细胞增殖（cell proliferation）与凋亡（apoptosis）过程。上述通用通路与MO3.13细胞中铜色酮诱导的细胞毒性（cytotoxicity）相关，提示该蛋白质组学方法或可用于对抗铜色酮的毒性效应。综上，尽管利用铜色酮构建少突胶质细胞毒性模型无法完全覆盖少突胶质细胞损伤的全部病理生理学（pathophysiology）机制，但本研究结果为解析大麻二酚与抗精神病药对抗铜色酮毒性的相关机制提供了新视角，也为髓鞘相关过程与缺损（myelin-related processes and deficits）的研究指明了新方向。