title: Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: implication for antioxidative psychotropic actions via microglia.
abstract: 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-γ-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.
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan. takahiro@npsych.med.kyushu-u.ac.jp
authors.forename: Takahiro A
authors.initials: TA
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Monji
authors.forename: Keiji
authors.initials: K
authors.lastname: Yasukawa
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Mizoguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Horikawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Seki
authors.forename: Sadayuki
authors.initials: S
authors.lastname: Hashioka
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Han
authors.forename: Mina
authors.initials: M
authors.lastname: Kasai
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sonoda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hirata
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Inoguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy; D017628:Microglia / Q000187:drug effects*; D019255:NADPH Oxidases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D013481:Superoxides; D000068180:Aripiprazole; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium