Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic

Aripiprazole (ARP) is a partial agonist of dopamine D2 receptors that is commonly prescribed to treat schizophrenia and bipolar disorder. The anti-inflammatory effect of ARP was recently documented in a few studies, but its molecular mechanisms have not been fully elucidated. In this study, peptidoglycan (PGN)-treated macrophages (RAW264.7 cells), reporter gene assay, an overexpression strategy, immuno-precipitation, and immunoblotting analysis were employed to clarify the anti-inflammatory mechanism of ARP. ARP was found to dose-dependently inhibit production of nitric oxide (NO) and prostaglandin E-2 (PGE(2)) without exhibiting cytotoxicity. In agreement with this result, ARP was found to suppress the mRNA expression levels of inflammatory genes such as cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and tumor necrosis factor (TNE)-alpha. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1) and nuclear factor (NF)-kappa B are targeted by ARP. Similar to these data, c-Jun N-terminal kinase (INK), mitogen-activated protein kinase kinase 4 (MKK4), MKK7, and transforming growth factor beta-activated kinase 1 (TAK1) for AP-1 activation, and inhibitor of kappa B alpha (I kappa B alpha), IicBcekinase alpha/beta (IKK alpha/beta), AKT, phosphatidylinositide 3-kinases (1313K), spleen tyrosine kinase (Syk), and Src for NF-kappa B activation were revealed to be inhibited by ARP treatment. These results suggest that ARP can suppress inflammatory responses triggered by Gram positive bacteria through suppression of both AP-1 and NE-kappa B pathways. (C) 2017 Elsevier Inc. All rights reserved.