Jang Soyong, Jung Jae-Chul, Kim Dong Hyun, Ryu Jong Hoon, Lee Yongnam, Jung Mankil, Oh Seikwan
Department of Neuroscience, School of Medicine, Ewha Womans University, Seoul, Korea.
J Pharmacol Exp Ther. 2009 Feb;328(2):435-47. doi: 10.1124/jpet.108.144014. Epub 2008 Nov 4.
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.
为了寻找新的神经保护化合物，合成了新型亚苄基苯乙酮化合物（JCI，(3E)-4-(4-羟基-3-甲氧基苯基)丁-3-烯-2-酮；JC2，(1E)-1-(4-羟基-3-甲氧基苯基)庚-1-烯-3-酮；JC3，(2E)-3-(4-羟基-3-甲氧基苯基)苯丙烯-2-烯-1-酮；JC4，(1E)-1-(4-羟基-3-甲氧基苯基)-5-苯基戊-1-烯-3-酮；JC5，(1E)-3-(4-羟基-3-甲氧基苯基)-6-苯基己-1-烯-3-酮；JC6，(1E)-1-(4-羟基-3-甲氧基苯基)-7-苯基庚-1-烯-3-酮），并评估了它们预防神经毒性的潜力。所有化合物（JC1 - JC6）在清除自由基、抑制皮质细胞中谷氨酸诱导的神经毒性以及抑制小胶质细胞中脂多糖（LPS）诱导的一氧化氮（NO）生成方面均显示出显著效果。(2E)-3-(4-羟基-3-甲氧基苯基)苯丙烯-2-烯-1-酮（JC3）在使用器官型海马培养和大脑中动脉闭塞（MCAO）的缺血模型中表现出最有效的神经保护作用。基于上述结果，使用皮质神经元细胞和小胶质细胞确定了表现出强大抗兴奋毒性和抗炎作用的JC3生物活性的潜在机制。化合物JC3对培养的皮质细胞中氧-葡萄糖剥夺和过氧化氢诱导的细胞毒性具有神经保护作用。此外，它抑制了LPS处理的小胶质细胞中NO、促炎细胞因子和活性氧的生成。它还抑制了小鼠MCAO 3天后活化小胶质细胞以及皮质和纹状体中磷酸化的Janus酪氨酸激酶2/磷酸化的信号转导和转录激活因子3以及丝裂原活化蛋白激酶（MAPK）的激活。这些结果表明JC3可能影响一组细胞内信号级联反应，包括Janus酪氨酸激酶/信号转导和转录激活因子以及MAPK途径。这项研究表明亚苄基苯乙酮衍生物可能是有用的抗神经毒性药物。
