A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes A beta-inhibition of the cascade in cultured rat CNS neurons

作者：Al Rahim Md; Nakajima Akira; Misawa Norihiko; Shindo Kazutoshi; Adachi Kyoko; Shizuri Yoshikazu; Ohizumi Yasushi; Yamakuni Tohru^*

来源：European Journal of Pharmacology, 2008, 600(1-3): 10-17.

DOI：10.1016/j.ejphar.2008.09.046

• Chalcone-diol
• A beta [amyloid beta-peptide]
• ERK [extracellular signal-regulated kinase]
• CREB [cAMP-response element-binding protein]
• CNS [central nervous system] neuronal culture

Chalcone compounds have been widely studied for their anti-inflammatory, anti-pyretic, anti-invasive and anti-proliferative activities in various cell lines. However, their effects on the central nervous system (CNS) are still largely unexplored. We have recently developed a bioconversion system using a recombinant Escherichia coli that enables its to produce chemical compounds that are naturally rare and usually difficult to chemically synthesize. One such compound is 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, a novel chalcone-diol. Here we show, for the first time, that the chalcone-diol enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) in a time- and concentration-dependent manner in cultured cortical neurons. Also, this chalcone-diol increased intracellular cyclic AMP (cAMP) concentration, thereby enhancing phosphorylation of ERK and cAMP-response element-binding protein (CREB), and CRE-mediated transcription via the cAMP-dependent protein kinase (PKA)/mitogen-activated protein kinase/ERK kinase (MEK) pathway in cultured rat hippocampal neurons. Recent studies have demonstrated that PKA/CRE B-dependent signaling, which is required for long-term potentiation, is inhibited by sublethal concentrations of amyloid beta-peptide (A beta) in cultured hippocampal neurons. After treatment with the chalcone-diol at 50 mu M prior to treatment with a sublethal concentration of A beta(1-42), the A beta(1-42)-induced inhibition of phosphorylation of PKA substrates and CREB was prevented in cultured hippocampal neurons, indicating the potential for protection against the A beta-induced impairment of PKA/CREB signaling observed in Alzheimer's disease. Therefore, these results suggest that our present study provides a new approach for discovering novel lead compounds for the treatment of neurodegenerative CNS diseases associated with impaired PKA/CREB signaling, including Alzheimer's disease.

• 出版日期2008-12-14