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A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Abeta-inhibition of the cascade in cultured rat CNS neurons.
Eur J Pharmacol. 2008 Dec 14; 600(1-3):10-7.EJ

Abstract

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 us 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/CREB-dependent signaling, which is required for long-term potentiation, is inhibited by sublethal concentrations of amyloid beta-peptide (Abeta) in cultured hippocampal neurons. After treatment with the chalcone-diol at 50 muM prior to treatment with a sublethal concentration of Abeta(1-42), the Abeta(1-42)-induced inhibition of phosphorylation of PKA substrates and CREB was prevented in cultured hippocampal neurons, indicating the potential for protection against the Abeta-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.

Authors+Show Affiliations

Department of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Sendai, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18948095

Citation

Al Rahim, Md, et al. "A Novel Diol-derivative of Chalcone Produced By Bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, Activates PKA/MEK/ERK Signaling and Antagonizes Abeta-inhibition of the Cascade in Cultured Rat CNS Neurons." European Journal of Pharmacology, vol. 600, no. 1-3, 2008, pp. 10-7.
Al Rahim M, Nakajima A, Misawa N, et al. A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Abeta-inhibition of the cascade in cultured rat CNS neurons. Eur J Pharmacol. 2008;600(1-3):10-7.
Al Rahim, M., Nakajima, A., Misawa, N., Shindo, K., Adachi, K., Shizuri, Y., Ohizumi, Y., & Yamakuni, T. (2008). A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Abeta-inhibition of the cascade in cultured rat CNS neurons. European Journal of Pharmacology, 600(1-3), 10-7. https://doi.org/10.1016/j.ejphar.2008.09.046
Al Rahim M, et al. A Novel Diol-derivative of Chalcone Produced By Bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, Activates PKA/MEK/ERK Signaling and Antagonizes Abeta-inhibition of the Cascade in Cultured Rat CNS Neurons. Eur J Pharmacol. 2008 Dec 14;600(1-3):10-7. PubMed PMID: 18948095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Abeta-inhibition of the cascade in cultured rat CNS neurons. AU - Al Rahim,Md, AU - Nakajima,Akira, AU - Misawa,Norihiko, AU - Shindo,Kazutoshi, AU - Adachi,Kyoko, AU - Shizuri,Yoshikazu, AU - Ohizumi,Yasushi, AU - Yamakuni,Tohru, Y1 - 2008/10/09/ PY - 2008/05/29/received PY - 2008/09/25/revised PY - 2008/09/29/accepted PY - 2008/10/25/pubmed PY - 2009/3/28/medline PY - 2008/10/25/entrez SP - 10 EP - 7 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 600 IS - 1-3 N2 - 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 us 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/CREB-dependent signaling, which is required for long-term potentiation, is inhibited by sublethal concentrations of amyloid beta-peptide (Abeta) in cultured hippocampal neurons. After treatment with the chalcone-diol at 50 muM prior to treatment with a sublethal concentration of Abeta(1-42), the Abeta(1-42)-induced inhibition of phosphorylation of PKA substrates and CREB was prevented in cultured hippocampal neurons, indicating the potential for protection against the Abeta-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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/18948095/A_novel_diol_derivative_of_chalcone_produced_by_bioconversion_3__23_dihydroxyphenyl__1_phenylpropan_1_one_activates_PKA/MEK/ERK_signaling_and_antagonizes_Abeta_inhibition_of_the_cascade_in_cultured_rat_CNS_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)01015-7 DB - PRIME DP - Unbound Medicine ER -