Received for publication July 25, 2008.
Revised November 3, 2008.
Accepted for publication November 3, 2008.

The neuroprotective effects of benzylideneacetophenone derivatives on excitotoxicity and inflammation via pJAK2/pSTAT3 and MAPK pathways

Abstract

To search for new neuroprotective compounds, novel benzylideneacetophenone compounds (JC1-JC6) 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-l-one (JC3) exhibited the most potent neuroprotective effect in ischemia model using organotypic hippocampal culture (OHC) and middle cerebral artery occlusion (MCAO). Based on the above results, the mechanisms underlying the biological activity of JC3, which exhibited potent anti-excitotoxic and anti-inflammatory effects, were determined using cortical neurons and microglia. Compound JC3 exerted a neuroprotective effect on oxygen-glucose deprivation (OGD)- and hydrogen peroxide (H₂O₂)-induced cytotoxicity in cultured cortical cells. In addition, it suppressed the generation of NO, pro-inflammatory cytokines, and reactive oxygen species (ROS) in LPS-treated microglial cells. It also suppressed the activation of pJAK2/pSTAT3 and MAPK in activated microglia 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 (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways. This study suggests that benzylideneacetophenone derivative could be useful anti-neurotoxic agents.

Key words: Janus tyrosine kinase, MAPK, benzylideneacetophenone, inflammation, neuroprotection, oxygen-glucose deprivation