title: Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo.
abstract: The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks. Stem Cells 2017;35:458-472.
authors.affiliation: Instituto de Investigaciones Biomédicas (CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jose A
authors.identifier: 0000-0001-9008-0056
authors.initials: JA
authors.lastname: Morales-Garcia
authors.affiliation: Departamento de Psicobiologia, Facultad de Psicología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Echeverry-Alzate
authors.affiliation: Instituto de Investigaciones Biomédicas (CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.affiliation: Instituto de Investigaciones Biomédicas (CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Sanz-SanCristobal
authors.affiliation: Departamento de Psicobiologia, Facultad de Psicología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lopez-Moreno
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Santos
authors.affiliation: Instituto de Investigaciones Biomédicas (CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development*; D020547:Lateral Ventricles / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development*; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017208:Rats, Wistar; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D010726:Phosphodiesterase Inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7
keywords: Adult neurogenesis; Hippocampus; Phosphodiesterase7; Subventricular zone