Effects of thiazole derivative drugs on inflammation-mediated degeneration of neuronal cells

Abstract

Central nervous system (CNS) inflammation mediated by activation of microglia has been known as one of the key events in the early stages of the development of neurodegenerative diseases. Fully effective anti-neuroinflammatory strategies have not yet been developed despite the abundance of data on the subject and so the systematic search for new anti-neuroinflammatory compounds is still matter of intense research. I have been interested in the development of effective anti-neuroinflammatory drugs, and have examined various thiazole derivatives in neuronal cells. Thiazole derivatives are very interesting molecules for drug development, because they have been previously shown to be useful for treating various diseases, including neurodegenerative disorders. However, its mechanisms of action have not yet been completely elucidated. In addition, testing structurally distinct classes will be necessary to strengthen our therapeutic concept. In this study, I investigated the effects of thiazole derivative drugs (KHG21834, KHG25857, KHG25967, or KHG24033) on β-amyloid (Aβ)-, lipopolysaccharide (LPS)-, glutamate-, or oxidative stress-induced neuroinflammation. In vitro and in vivo studies showed that thiazole derivatives effectively prevented inflammatory stimuli-induced intracellular Ca2+ influx and reduced the subsequent overproduction of tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), nitric oxide (NO), reactive oxygen species (ROS), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Thiazole derivatives blocked the mitogen-activated protein kinases (MAPK), NF-kB and Wnt signaling pathway. Furthermore, thiazole derivatives preserved the mitochondrial potential and inhibited the overproduction of cytochrome c. Thiazole derivatives inhibited Aβ-induced apoptosis in neuronal cells. Thiazole derivatives attenuated the H2O2-induced reductions in superoxide dismutase (SOD), catalase, glutathione (GSH) and glutathione peroxidase (GSH-px) activities. Thiazole derivatives also reduced H2O2-induced increases in ROS levels, and malondialdehyde (MDA) content. The results in the present work showed that thiazole derivates effectively protected against Aβ-, LPS-, glutamate-, or oxidative stress-induced neuroinflammation. Among the drugs tested, KHG25857 showed the best anti-inflammatory effects on neuronal cells both in vitro and in vivo, suggesting a therapeutic potential for this compound in neurodegenerative diseases.