title: 12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation.
abstract: BACKGROUND
  Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system.
  
  
  METHODS
  We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain.
  
  
  RESULTS
  We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo.
  
  
  CONCLUSIONS
  This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal.
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Noelia
authors.initials: N
authors.lastname: Geribaldi-Doldán
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Eugenia
authors.initials: E
authors.lastname: Flores-Giubi
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Maribel
authors.initials: M
authors.lastname: Murillo-Carretero
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Bernal
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Manuel
authors.initials: M
authors.lastname: Carrasco
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Macías-Sánchez
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Jesús
authors.initials: J
authors.lastname: Domínguez-Riscart
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Cristina
authors.initials: C
authors.lastname: Verástegui
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui).
authors.forename: Rosario
authors.initials: R
authors.lastname: Hernández-Galán
authors.affiliation: Area de Fisiología, Facultad de Medicina, Universidad de Cadiz, Cádiz, Spain (Mrs Geribaldi-Doldán, Mrs Flores-Giubi, Dr Murillo-Carretero, Mr García-Bernal, Dr Carrasco, Dr Domínguez-Riscart, and Dr Castro); Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain (Mrs Flores-Giubi, Dr Macías-Sánchez, and Dr Hernández-Galán); Departamento de Anatomía y Embriología Humana, Universidad de Cádiz, Cádiz, Spain (Dr Verástegui). carmen.castro@uca.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D010703:Phorbol Esters; C119222:phorbol-12-myristate; C070999:prostratin; D011493:Protein Kinase C; D001973:Bromodeoxyuridine
keywords: 12-deoxyphorbol; PKC; neural progenitor cells; neurogenesis; prostratin