Inhibitory effects of aripiprazole on interferon-γ-induced microglial activation via intracellular Ca2+ regulation in vitro
Inhibitory effects of aripiprazole on interferon-γ-induced microglial activation via intracellular Ca2+ regulation in vitro
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DOI：
10.1111/j.1471-4159.2008.05435.x
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Kanba, Shigenobu
中科院分区：
文献类型：
--
作者：
Kato, Takahiro;Mizoguchi, Yoshito;Kanba, Shigenobu
炎症/免疫反应系统的激活被认为与精神分裂症的病理生理有关。阿立哌唑是一种新型的非典型抗精神病药，是一种高亲和力的多巴胺D-2受体部分激动剂。非典型抗精神病药物，所有这些都有多巴胺D-2受体拮抗作用，最近报道有显着抑制干扰素（IFN）-γ诱导的小胶质细胞激活在体外的影响。在本研究中，我们研究了阿立哌唑是否也对IFN-γ诱导的小胶质细胞活化具有抗炎作用。阿立哌唑可显著抑制IFN-γ激活的小胶质细胞产生一氧化氮（NO）和肿瘤坏死因子（TNF）-α，并抑制IFN-γ诱导的鼠小胶质细胞内Ca 2+浓度（[Ca 2 +]（i））升高，而非喹吡罗（多巴胺D-2完全激动剂）。据报道，增加的[Ca 2 +]（i）对于NO和某些细胞因子的释放是必需的，但本身并不足够。因此，我们可以推测阿立哌唑可能通过抑制IFN-γ诱导的小胶质细胞[Ca 2 +]（i）升高来抑制IFN-γ诱导的小胶质细胞活化。我们的研究结果表明，不仅具有多巴胺D-2受体拮抗作用的抗精神病药物，而且阿立哌唑也通过抑制小胶质细胞活化而具有抗炎作用。因此，抗精神病药物可能通过减少小胶质细胞炎症反应对精神分裂症患者具有潜在的有用的治疗作用。
The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D-2 receptor partial agonist. Atypical antipsychotics, all of which have dopamine D-2 receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-gamma-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-gamma-induced microglial activation. Not quinpirole, dopamine D-2 full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha from IFN-gamma-activated microglia and suppressed the IFN-gamma-induced elevation of intracellular Ca2+ concentrations ([Ca2+](i)) in murine microglial cells. Increased [Ca2+](i) has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-gamma-induced microglial activation through the suppression of IFN-gamma-induced elevation of [Ca2+](i) in microglia. Our results demonstrated that not only antipsychotics which have dopamine D-2 receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions.