Abstract
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.
Footnotes
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This work was supported by BioGreen 21 Program, Rural Development Administration, Republic of Korea [Grant 20070301-034-026-007-04].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144014.
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ABBREVIATIONS: MCAO, middle cerebral artery occlusion; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; IL, interleukin; H2O2, hydrogen peroxide; LPS, lipopolysaccharide; MEM, modified Eagle's medium; FBS, fetal bovine serum; DIV, days in vitro; LDH, lactate dehydrogenase; WST-1, 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate; OHC, organotypic hippocampal slice culture; HBSS, Hanks' balanced salt solution; PI, propidium iodide; OGD, oxygen-glucose deprivation; PCR, polymerase chain reaction; iNOS, inducible nitric-oxide synthase; 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; PBS, phosphate-buffered saline; JAK, Janus tyrosine kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; p, phosphorylated; ROS, reactive oxygen species; H2DCF-DA, dichlorodihydrofluorescein diacetate; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); AG490, α-cyano-(3,4-dihydroxy)-N-benzylcinnamide.
- Received July 24, 2008.
- Accepted November 3, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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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
