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NEUROPHARMACOLOGY

The Neuroprotective Effects of Benzylideneacetophenone Derivatives on Excitotoxicity and Inflammation via Phosphorylated Janus Tyrosine Kinase 2/Phosphorylated Signal Transducer and Activator of Transcription 3 and Mitogen-Activated Protein K Pathways

Department of Neuroscience and Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea (S.J., J.-C.J., S.O.); Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Korea (D.H.K., J.H.R.); and Department of Chemistry, Yonsei University, Seoul, Korea (Y.L., M.J.)

To search for new neuroprotective compounds, novel benzylideneacetophenone compounds (JCI, (3E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one; JC2, (1E)-1-(4-hydroxy-3-methoxyphenyl)hept-1-en-3-one; JC3, (2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one; JC4, (1E)-1-(4-hydroxy-3-methoxyphenyl)-5-phenylpent-1-en-3-one; JC5, (1E)-3-(4-hydroxy-3-methoxyphenyl)-6-phenylhex-1-en-3-one; JC6, (1E)-1-(4-hydroxy-3-methoxyphenyl]-7-phenylhept-1-en-3-one) were synthesized, and their potential to prevent neurotoxicities were evaluated. All compounds (JC1–JC6) showed considerable effect on free radical scavenging, the inhibition of glutamate-induced neurotoxicity in cortical cells, and the suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) generation in microglia. (2E)-3-(4-Hydroxy-3-methoxyphenyl)-phenylpro-2-en-1-one (JC3) exhibited the most potent neuroprotective effect in ischemia model using organotypic hippocampal culture and middle cerebral artery occlusion (MCAO). Based on the above-mentioned results, the mechanisms underlying the biological activity of JC3, which exhibited potent antiexcitotoxic and anti-inflammatory effects, were determined using cortical neuronal cells and microglia. Compound JC3 exerted a neuroprotective effect on oxygen-glucose deprivation- and hydrogen peroxide-induced cytotoxicity in cultured cortical cells. In addition, it suppressed the generation of NO, proinflammatory cytokines, and reactive oxygen species in LPS-treated microglial cells. It also suppressed the activation of phosphorylated Janus tyrosine kinase 2/phosphorylated signal transducer and activator of transcription 3 and mitogen-activated protein kinase (MAPK) in activated microglia and in cortex and striatum after 3 days of the MCAO in mice. These results demonstrated that JC3 might affect a set of intracellular signaling cascades, including the Janus tyrosine kinase/signal transducers and activators of transcription and MAPK pathways. This study suggests that benzylideneacetophenone derivative could be useful antineurotoxic agents.

Address correspondence to: Dr. Seikwan Oh, Department of Neuroscience, School of Medicine, Ewha Womans University, Mok-dong, Yangchon-ku, Seoul 158-710 Korea. E-mail: skoh{at}ewha.ac.kr