Aberrant neuro-immune responses are involved in abnormalities of epigenetic mechanisms in schizophrenia.

近年来的影像学研究表明，精神分裂症的病理生理与脑白质异常和小胶质细胞活化密切相关。此外，临床试验表明，二甲胺四环素，一种抑制小胶质细胞激活的抗生素，改善精神分裂症的症状。我们不仅报道了多巴胺D2受体（D2R）拮抗的非典型抗精神病药物，也报道了阿立哌唑。一种独特的抗精神病药物，具有D2R部分激动作用，体外抑制小胶质细胞活化。因此，抗精神病药物可能对小胶质细胞和少突胶质细胞都有有益的影响，但这些机制尚未明确。本研究采用小胶质细胞和少突胶质细胞共培养模型，探讨抗精神病药物是否通过抑制小胶质细胞活化来抑制少突胶质细胞损伤。阿立哌唑和米诺环素可抑制干扰素-γ (IFN-γ)激活的小胶质细胞共培养模型中少突胶质细胞的凋亡，而传统抗精神病药物氟哌啶醇则没有作用。阿立哌唑和米诺环素抑制IFN-γ激活的小胶质细胞产生肿瘤坏死因子α (TNF-α)。此外，阿立哌唑和米诺环素可减弱小胶质细胞中信号转导因子和转录激活因子1 （STAT1）的磷酸化。总之，我们的研究结果表明，阿立哌唑和米诺环素可能通过减少小胶质细胞激活引起的少突胶质细胞损伤而具有抗精神病作用。这些结果为精神分裂症研究提出了一种新的治疗假设。未来的体内研究也应该进行，以证实目前的结果。

Recent imaging studies have indicated that the pathophysiology of schizophrenia is closely related to white matter abnormalities and microglial activation. Additionally, clinical trials have suggested that minocycline, an antibiotic with inhibitory effects on microglial activation, improves symptoms of schizophrenia. We have reported that not only atypical antipsychotics with dopamine D2 receptor (D2R) antagonism but also aripiprazole. A unique antipsychotic drug with D2R partial agonism, inhibit microglial activation in vitro. Thus, antipsychotics may exert a beneficial influence on both of microglia and oligodendrocytes, while these mechanisms have not been clarified. Here, we investigated whether antipsychotics suppress oligodendrocyte damage by supressing microglial activation utilizing co-culture model with microglia and oligodendrocytes. Aripiprazole and minocycline suppressed the apoptosis of the oligodendrocytes in the co-culture model with interferon-γ (IFN-γ)-activated microglia, while haloperidol, a traditional antipsychotic drug, did not. Aripiprazole and minocycline inhibited the production of tumor necrosis factor-alpha (TNF-α) from IFN-γ-activated microglia. Moreover, aripiprazole and minocycline attenuated the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in microglia. Overall, our results suggest that aripiprazole and minocycline may have antipsychotic effects through reducing oligodendrocyte damage caused by microglial activation. These results put forward a novel therapeutic hypothesis in schizophrenia research. Future in vivo studies to confirm the present results should also be performed.