{"doi":"10.3389/fcell.2020.599389","title":"A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway","abstract":"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.","journal":"Frontiers in Cell and Developmental Biology","year":2020,"id":93081,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":466425,"name":"Shichao Gao","orcid":null,"position":1,"is_corresponding":false},{"id":465245,"name":"Victor Zheng","orcid":"0000-0001-9640-2204","position":2,"is_corresponding":false},{"id":465246,"name":"Ling Chen","orcid":"0000-0003-1934-5992","position":3,"is_corresponding":false},{"id":465247,"name":"Min Ma","orcid":"0000-0002-4203-5215","position":4,"is_corresponding":false},{"id":466426,"name":"Shichen Shen","orcid":null,"position":5,"is_corresponding":false},{"id":294893,"name":"Jun Qu","orcid":"0000-0002-1346-6809","position":6,"is_corresponding":false},{"id":465248,"name":"Hanting Zhang","orcid":"0000-0002-4208-3786","position":7,"is_corresponding":false},{"id":257969,"name":"Mark E. Gurney","orcid":"0000-0003-4901-3083","position":8,"is_corresponding":false},{"id":465249,"name":"James M. O’Donnell","orcid":"0000-0002-8994-7588","position":9,"is_corresponding":false},{"id":319897,"name":"Ying Xu","orcid":"0000-0001-5479-7922","position":10,"is_corresponding":false},{"id":291290,"name":"Yulu Wang","orcid":"0000-0003-0760-6649","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-18T22:30:54.208860Z","pmid":"33363155","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}