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.
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.
Jang
Soyong
S
Department of Neuroscience, School of Medicine, Ewha Womans University, Seoul, Korea.
Jung
Jae-Chul
JC
Kim
Dong Hyun
DH
Ryu
Jong Hoon
JH
Lee
Yongnam
Y
Jung
Mankil
M
Oh
Seikwan
S
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000517:prevention & control; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D011427:Propiophenones / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
C532465:(2E)-3-(4-hydroxy-3-methoxyphenyl) phenylpro-2-1-one; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D011427:Propiophenones; D014157:Transcription Factors; C060759:enhancer-binding protein AP-3; D009569:Nitric Oxide; D018698:Glutamic Acid; D002599:Chalcone; D006861:Hydrogen Peroxide; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases