Sharma Kapil, Dev Kumlesh K
Drug Development Research Group, Department of Physiology, School of Medicine, Trinity College Dublin, D02 R590 Dublin, Ireland.
Biomedicines. 2023 Apr 28;11(5):1313. doi: 10.3390/biomedicines11051313.
The role of altered myelin in the onset and development of schizophrenia and changes in myelin due to antipsychotics remains unclear. Antipsychotics are D receptor antagonists, yet D receptor agonists increase oligodendrocyte progenitor numbers and limit oligodendrocyte injury. Conflicting studies suggest these drugs promote the differentiation of neural progenitors to oligodendrocyte lineage, while others report antipsychotics inhibit the proliferation and differentiation of oligodendrocyte precursors. Here, we utilised in-vitro (human astrocytes), ex-vivo (organotypic slice cultures) and in-vivo (twitcher mouse model) experimental study designs of psychosine-induced demyelination, a toxin that accumulates in Krabbe disease (KD), to investigate direct effects of antipsychotics on glial cell dysfunction and demyelination. Typical and atypical antipsychotics, and selective D and 5HT receptor antagonists, attenuated psychosine-induced cell viability, toxicity, and morphological aberrations in human astrocyte cultures. Haloperidol and clozapine reduced psychosine-induced demyelination in mouse organotypic cerebellar slices. These drugs also attenuated the effects of psychosine on astrocytes and microglia and restored non-phosphorylated neurofilament levels, indicating neuroprotective effects. In the demyelinating twitcher mouse model of KD, haloperidol improved mobility and significantly increased the survival of these animals. Overall, this study suggests that antipsychotics directly regulate glial cell dysfunction and exert a protective effect on myelin loss. This work also points toward the potential use of these pharmacological agents in KD.
髓鞘改变在精神分裂症发病和发展中的作用以及抗精神病药物导致的髓鞘变化仍不清楚。抗精神病药物是D受体拮抗剂，但D受体激动剂可增加少突胶质前体细胞数量并限制少突胶质细胞损伤。相互矛盾的研究表明，这些药物促进神经祖细胞向少突胶质细胞谱系分化，而其他研究报告称抗精神病药物会抑制少突胶质前体细胞的增殖和分化。在这里，我们利用体外（人星形胶质细胞）、离体（器官型切片培养）和体内（震颤小鼠模型）实验研究设计，研究精神鞘氨醇诱导的脱髓鞘作用，精神鞘氨醇是一种在克拉伯病（KD）中积累的毒素，以研究抗精神病药物对胶质细胞功能障碍和脱髓鞘的直接影响。典型和非典型抗精神病药物以及选择性D和5-羟色胺受体拮抗剂可减轻精神鞘氨醇诱导的人星形胶质细胞培养物中的细胞活力、毒性和形态异常。氟哌啶醇和氯氮平可减少精神鞘氨醇诱导的小鼠器官型小脑切片中的脱髓鞘。这些药物还减弱了精神鞘氨醇对星形胶质细胞和小胶质细胞的影响，并恢复了非磷酸化神经丝水平，表明具有神经保护作用。在KD的脱髓鞘震颤小鼠模型中，氟哌啶醇改善了运动能力并显著提高了这些动物的存活率。总体而言，本研究表明抗精神病药物可直接调节胶质细胞功能障碍并对髓鞘损失发挥保护作用。这项工作还指出了这些药物在KD中的潜在用途。
