Animals; Cognition; Dentate Gyrus; Hippocampus; Mice; Neurons; Neural Stem Cells; Neurogenesis; Pharmacology; Psychiatry and Mental Health
Abstract :
[en] Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the dentate gyrus of the hippocampus (DG) integrate in hippocampal circuitry participating in memory tasks. Several neurological and neuropsychiatric disorders show cognitive impairment together with a reduction in DG neurogenesis. Growth factors secreted within the DG promote neurogenesis. Protein kinases of the protein kinase C (PKC) family facilitate the release of several of these growth factors, highlighting the role of PKC isozymes as key target molecules for the development of drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show in here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and in the DG of mice, affecting neuroblasts differentiation and neuronal maturation. A concomitant improvement in learning and spatial memory tasks performance can be observed. Insights into the mechanism of action reveal that this compound facilitates classical PKCα activation and promotes transforming growth factor alpha (TGFα) and, to a lesser extent, neuregulin release. Our results highlight the role of this molecule in the development of pharmacological drugs to treat neurological and neuropsychiatric disorders associated with memory loss and a deficient neurogenesis.
Domínguez-García, Samuel ✱; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Gómez Oliva, Ricardo ✱; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Geribaldi-Doldán, Noelia; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Hierro-Bujalance, Carmen; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Sendra, Marta; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigaciones Marinas (IIM-CSIC), Vigo, Pontevedra, Spain
Ruiz, Félix A; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Área de Nutrición, Facultad de Medicina Universidad de Cádiz, Cádiz, Spain
Carrascal, Livia; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
Macías-Sánchez, Antonio J; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Spain
Verástegui, Cristina; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Anatomía y Embriología Humanas, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
Hernández-Galán, Rosario; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Spain
García-Alloza, Mónica; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Nunez-Abades, Pedro; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
Castro, Carmen ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. carmen.castro@uca.es ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain. carmen.castro@uca.es
This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (grant numbers RTI-2018-099908-BC21 granted to CC and RTI-2018-099908-B-C22 granted to RGH), and MICINN/FEDER granted to CC and BFU2016-75038R granted to MGA) and Consejería de Economía, Conocimiento, Empresas y Universidades (grant number FEDER-UCA18-106647). Authors claim no competing interests.
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