title: Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro.
abstract: 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 Ca(2+) concentrations ([Ca(2+)](i)) in murine microglial cells. Increased [Ca(2+)](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 [Ca(2+)](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.
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kato
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Mizoguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Monji
authors.forename: Hideki
authors.initials: H
authors.lastname: Horikawa
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Seki
authors.forename: Toru
authors.initials: T
authors.lastname: Iwaki
authors.forename: Sadayuki
authors.initials: S
authors.lastname: Hashioka
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*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009474:Neurons; D009569:Nitric Oxide / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D014409:Tumor Necrosis Factor-alpha; D019257:Quinpirole; D009569:Nitric Oxide; D007371:Interferon-gamma; D000068180:Aripiprazole; D002118:Calcium