Anti-inflammatory mechanisms of N-adamantyl-4-methylthiazol-2-amine in lipopolysaccharide-stimulated BV-2 microglial cells

Abstract

The activation of microglia is crucially associated with the neurodegeneration observed in many neuro-inflammatory pathologies, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. We have examined various thiazole derivatives with the goal of developing new anti-neuroinflammatory drugs. Thiazole derivatives are attractive candidates for drug development, because they are efficiently synthesized and active against a number of disease organisms and conditions, including neurodegenerative disorders. The present study investigated the effects of a new compound, N-adamantyl-4-methylthiazol-2-amine (KHG26693), against lipopolysaccharide (LPS)-induced inflammation in cultured BV-2 microglial cells. KHG26693 suppressed several inflammatory responses in LPS-activated cells, as evidenced by decreased levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), hydrogen peroxide (H2O2), reactive oxygen species (ROS), nitric oxide (NO), and lipid peroxidation. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) content, but not as a result of the upregulation of superoxide dismutase (SOD) or catalase activity. The pharmacological properties of KHG26693 were also facilitated via inhibition of both the cluster of differentiation 14 (CD14)/toll-like receptor 4 (TLR4)-dependent nuclear factor kappa B (NF-kappa B) signaling pathway and extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, KHG26693 successfully blocked the migration of LPS-activated microglia, most likely by modulating the ERK pathway. Taken together, these results demonstrate that the anti-inflammatory and antioxidative actions of KHG26693 are mediated, at least in part, through the control of microglial activation. (C) 2014 Elsevier B.V. All rights reserved.