A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway
A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an...
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2020.599389/full |
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| author | Yulu Wang Yulu Wang Shichao Gao Victor Zheng Ling Chen Ling Chen Ling Chen Min Ma Shichen Shen Jun Qu Hanting Zhang Hanting Zhang Mark E. Gurney James M. O’Donnell Ying Xu |
| author_facet | Yulu Wang Yulu Wang Shichao Gao Victor Zheng Ling Chen Ling Chen Ling Chen Min Ma Shichen Shen Jun Qu Hanting Zhang Hanting Zhang Mark E. Gurney James M. O’Donnell Ying Xu |
| author_sort | Yulu Wang |
| collection | DOAJ |
| description | A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders. |
| first_indexed | 2024-12-13T10:59:55Z |
| format | Article |
| id | doaj.art-b32281c76e4043ce81ec97cfa518955f |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-13T10:59:55Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-b32281c76e4043ce81ec97cfa518955f2022-12-21T23:49:19ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-12-01810.3389/fcell.2020.599389599389A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 PathwayYulu Wang0Yulu Wang1Shichao Gao2Victor Zheng3Ling Chen4Ling Chen5Ling Chen6Min Ma7Shichen Shen8Jun Qu9Hanting Zhang10Hanting Zhang11Mark E. Gurney12James M. O’Donnell13Ying Xu14College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesHangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Behavioral Medicine and Psychiatry, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United StatesDepartment of Physiology and Pharmacology, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United StatesDepartment of Cell Stress and Biophysical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesDepartment of Behavioral Medicine and Psychiatry, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United StatesDepartment of Physiology and Pharmacology, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United StatesTetra Therapeutics, Grand Rapids, MI, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United StatesA global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders.https://www.frontiersin.org/articles/10.3389/fcell.2020.599389/fullPDE4DBPN14770memoryhumanized PDE4D micecAMP/SIRT1/Akt/Bcl-2 pathway |
| spellingShingle | Yulu Wang Yulu Wang Shichao Gao Victor Zheng Ling Chen Ling Chen Ling Chen Min Ma Shichen Shen Jun Qu Hanting Zhang Hanting Zhang Mark E. Gurney James M. O’Donnell Ying Xu A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway Frontiers in Cell and Developmental Biology PDE4D BPN14770 memory humanized PDE4D mice cAMP/SIRT1/Akt/Bcl-2 pathway |
| title | A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway |
| title_full | A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway |
| title_fullStr | A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway |
| title_full_unstemmed | A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway |
| title_short | A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway |
| title_sort | novel pde4d inhibitor bpn14770 reverses scopolamine induced cognitive deficits via camp sirt1 akt bcl 2 pathway |
| topic | PDE4D BPN14770 memory humanized PDE4D mice cAMP/SIRT1/Akt/Bcl-2 pathway |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2020.599389/full |
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