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

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 mitogenactivated 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.The major pathogenic mechanisms of stroke include excitotoxicity, production of reactive free radicals, inflammation, and apoptosis (Mergenthaler et al., 2004). Activation of glutamate receptors, through the attendant failure of ion homeostasis and increase in intracellular Ca 2ϩ concentration, Article, publication date, and citation information can be found at

Benzylideneacetophenone derivatives attenuate IFN-γ-induced IP-10/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition

“…33, 34 In our present study, we showed that the IFN-γ-induced increases in IP-10/CXCL10 expression were reduced using 10 μ M JC3 monomer, 1 μ M dimer and 0.1 μ M trimer, those are comparable to doses used previously. 33, 34 However, to evaluate the anti-inflammatory activity of JC3 monomer or polymer in vivo , further research and preclinical studies are necessary to ensure the safety of JC3 treatment, and to determine the optimum dose of JC3 for the treatment of TAO.…”

“…32 One author of the current study (S. Oh) previously designed and synthesized novel benzylideneacetophenone derivatives (JC1 to JC5) on the basis of the structure of yakuchinone B, and showed that they exert a protective effect on brain ischemia both in vitro and in vivo . 33 In the present investigation, all compounds synthesized in this series (JC1 to JC5) showed considerable suppression of IFN-γ-induced IP-10/CXCL10 expression in orbital fibroblasts (data not shown). JC3, however, showed the greatest inhibitory effect, suppressing IFN-γ-induced IP-10/CXCL10 expression to a greater extent than yakuchinone B (Figure 3b).…”

“…Although we could not include in vivo experiments in this study, one author of this study (S. Oh) previously showed the anti-inflammatory and neuroprotective effects of JC3 in vivo using a mouse model of Parkinson's disease. 33, 34 In those studies, 10–30 μ M JC3 was effective in in vitro experiments, whereas mice tolerated JC3 at 10 mg kg −1 , administered at 24-h intervals for three consecutive days, or a single administration of JC3 (30 mg kg −1 ). 33, 34 In our present study, we showed that the IFN-γ-induced increases in IP-10/CXCL10 expression were reduced using 10 μ M JC3 monomer, 1 μ M dimer and 0.1 μ M trimer, those are comparable to doses used previously.…”

“…33, 34 In those studies, 10–30 μ M JC3 was effective in in vitro experiments, whereas mice tolerated JC3 at 10 mg kg −1 , administered at 24-h intervals for three consecutive days, or a single administration of JC3 (30 mg kg −1 ). 33, 34 In our present study, we showed that the IFN-γ-induced increases in IP-10/CXCL10 expression were reduced using 10 μ M JC3 monomer, 1 μ M dimer and 0.1 μ M trimer, those are comparable to doses used previously. 33, 34 However, to evaluate the anti-inflammatory activity of JC3 monomer or polymer in vivo , further research and preclinical studies are necessary to ensure the safety of JC3 treatment, and to determine the optimum dose of JC3 for the treatment of TAO.…”

A Benzylideneacetophenone Derivative Induces Apoptosis of Radiation-Resistant Human Breast Cancer Cells via Oxidative Stress

“…The benzylideneacetophenone derivative (1E)-1-(4-hydroxy-3-methoxyphenyl) hept-1-en-3-one (JC3) was discovered to be a neuroprotective agent against oxygen-glucose deprivation- and hydrogen peroxide-provoked cytotoxicity in cultured cortical cells (Jung et al ., 2008). In addition, JC3 potently activates intracellular signaling cascades including the Janus tyrosine (Jang et al ., 2009). …”