Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: Implication for antioxidative psychotropic actions via microglia
Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: Implication for antioxidative psychotropic actions via microglia
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DOI：
10.1016/j.schres.2011.03.019
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发表时间：
2011-07-01
影响因子：
4.5
通讯作者：
Kanba, Shigenobu
中科院分区：
文献类型：
--
作者：
Kato, Takahiro A.;Monji, Akira;Kanba, Shigenobu
抗氧化状态的改变与精神分裂症有关。小胶质细胞，自由基的主要来源，如超氧化物(。O（2)(-)）在各种脑病理中起着至关重要的作用。最近的尸检和影像学研究表明，精神分裂症患者的大脑中有小胶质细胞的激活。我们之前证明，非典型抗精神病药物包括阿立哌唑显著抑制干扰素γ刺激的小胶质细胞释放一氧化氮和促炎细胞因子。抗精神病药物通过调节小胶质细胞超氧化物产生的抗氧化作用从未报道过。因此，我们在此研究抗精神病药物对精神分裂症的影响。利用电子自旋共振（ESR）技术研究了PMA刺激的啮齿动物小胶质细胞O(2)（-）的生成，并通过细胞内Ca（2+）成像和免疫染色研究了细胞内机制。通过共培养实验研究了小胶质细胞活化对神经元的损伤作用。在各种抗精神病药物中，只有阿立哌唑能抑制。由pma刺激的小胶质细胞生成O(2)（-）。阿立哌唑被证明有抑制作用。O(2)（-）通过蛋白激酶C （PKC）激活、胞内Ca（2+）调节和NADPH氧化酶激活级联产生，通过细胞质p47（phox）易位到血浆/吞噬体膜。经阿立哌唑预处理后，pma刺激的小胶质细胞所引起的神经性串珠的形成被减弱。D2R拮抗剂长期以来被认为是精神分裂症的主要治疗作用。具有D2R部分激动作用的阿立哌唑与其他抗精神病药物一样有效，副作用更少，但阿立哌唑本身的治疗机制尚不清楚。本研究结果提示阿立哌唑可能通过降低小胶质细胞氧化反应和随后的神经元反应而具有精神药物作用，为精神分裂症研究提供了一种新的治疗假设。(C) 2011 Elsevier B.V.版权所有
Altered antioxidant status has been implicated in schizophrenia. Microglia, major sources of free radicals such as superoxide (.O(2)(-)), play crucial roles in various brain pathologies. Recent postmortem and imaging studies have indicated microglial activation in the brain of schizophrenic patients. We previously demonstrated that atypical antipsychotics including aripiprazole significantly inhibited the release of nitric oxide and proinflammatory cytokines from interferon-gamma-stimulated microglia in vitro. Antioxidative effects of antipsychotics via modulating microglial superoxide generation have never been reported. Therefore, we herein investigated the effects of antipsychotics on the .O(2)(-) generation from phorbol-myristate-acetate (PMA)-stimulated rodent microglia by the electron spin resonance (ESR) spectroscopy and also examined the intracellular mechanism by intracellular Ca(2+) imaging and immunostaining. Neuronal damage induced by microglial activation was also investigated by the co-culture experiment.Among various antipsychotics, only aripiprazole inhibited the .O(2)(-) generation from PMA-stimulated microglia. Aripiprazole proved to inhibit the .O(2)(-) generation through the cascade of protein kinase C (PKC) activation, intracellular Ca(2+) regulation and NADPH oxidase activation via cytosolic p47(phox) translocation to the plasma/phagosomal membranes. Formation of neuritic beading, induced by PMA-stimulated microglia, was attenuated by pretreatment of aripiprazole.D2R antagonism has long been considered as the primary therapeutic action for schizophrenia. Aripiprazole with D2R partial agonism is effective like other antipsychotics with fewer side effects, while aripiprazole's therapeutic mechanism itself remains unclear. Our results imply that aripiprazole may have psychotropic effects by reducing the microglial oxidative reactions and following neuronal reactions, which puts forward a novel therapeutic hypothesis in schizophrenia research. (C) 2011 Elsevier B.V. All rights reserved.