A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway

Frontiers in Cell and Developmental Biology

Min Ma³  Shichao Gao⁴  Yulu Wang⁴  Ying Xu⁴  Jun Qu⁴  Victor Zheng⁴  James M. O’Donnell⁴  Shichen Shen⁴  Hanting Zhang⁵  Ling Chen⁵  Mark E. Gurney⁷ 

[1] College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China;Department of Behavioral Medicine and Psychiatry, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United States;Department of Cell Stress and Biophysical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States;Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States;Department of Physiology and Pharmacology, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United States;Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China;Tetra Therapeutics, Grand Rapids, MI, United States;

关键词: PDE4D;    BPN14770;    memory;    humanized PDE4D mice;    cAMP/SIRT1/Akt/Bcl-2 pathway;   

DOI  :  10.3389/fcell.2020.599389

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown