Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease

Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulati...

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Autores principales: Ya-Jen Chiu, Te-Hsien Lin, Chiung-Mei Chen, Chih-Hsin Lin, Yu-Shan Teng, Chung-Yin Lin, Ying-Chieh Sun, Hsiu Mei Hsieh-Li, Ming-Tsan Su, Guey-Jen Lee-Chen, Wenwei Lin, Kuo-Hsuan Chang
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Publicado: Hindawi Limited 2021
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Acceso en línea:https://doaj.org/article/fd6296d700e147efb583f4a04c1de099
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spelling oai:doaj.org-article:fd6296d700e147efb583f4a04c1de0992021-11-22T01:11:34ZNovel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease1942-099410.1155/2021/3058861https://doaj.org/article/fd6296d700e147efb583f4a04c1de0992021-01-01T00:00:00Zhttp://dx.doi.org/10.1155/2021/3058861https://doaj.org/toc/1942-0994Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.Ya-Jen ChiuTe-Hsien LinChiung-Mei ChenChih-Hsin LinYu-Shan TengChung-Yin LinYing-Chieh SunHsiu Mei Hsieh-LiMing-Tsan SuGuey-Jen Lee-ChenWenwei LinKuo-Hsuan ChangHindawi LimitedarticleCytologyQH573-671ENOxidative Medicine and Cellular Longevity, Vol 2021 (2021)
institution DOAJ
collection DOAJ
language EN
topic Cytology
QH573-671
spellingShingle Cytology
QH573-671
Ya-Jen Chiu
Te-Hsien Lin
Chiung-Mei Chen
Chih-Hsin Lin
Yu-Shan Teng
Chung-Yin Lin
Ying-Chieh Sun
Hsiu Mei Hsieh-Li
Ming-Tsan Su
Guey-Jen Lee-Chen
Wenwei Lin
Kuo-Hsuan Chang
Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
description Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.
format article
author Ya-Jen Chiu
Te-Hsien Lin
Chiung-Mei Chen
Chih-Hsin Lin
Yu-Shan Teng
Chung-Yin Lin
Ying-Chieh Sun
Hsiu Mei Hsieh-Li
Ming-Tsan Su
Guey-Jen Lee-Chen
Wenwei Lin
Kuo-Hsuan Chang
author_facet Ya-Jen Chiu
Te-Hsien Lin
Chiung-Mei Chen
Chih-Hsin Lin
Yu-Shan Teng
Chung-Yin Lin
Ying-Chieh Sun
Hsiu Mei Hsieh-Li
Ming-Tsan Su
Guey-Jen Lee-Chen
Wenwei Lin
Kuo-Hsuan Chang
author_sort Ya-Jen Chiu
title Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
title_short Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
title_full Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
title_fullStr Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
title_full_unstemmed Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease
title_sort novel synthetic coumarin-chalcone derivative (e)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2h-chromen-2-one activates creb-mediated neuroprotection in aβ and tau cell models of alzheimer’s disease
publisher Hindawi Limited
publishDate 2021
url https://doaj.org/article/fd6296d700e147efb583f4a04c1de099
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