Effects of classical PKC activation on hippocampal neurogenesis and cognitive performance: mechanism of action

Abstract

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.

Targeting Protein Kinase C in Glioblastoma Treatment

“…For example, the proliferation of NSCs isolated from the SVZ of induced adult mice is stimulated with classical PKC activating diterpenes with a 12-deoxyphorbols or lathyrane structure [109,110,112]. This facilitates the ADAM17-mediated release of EGFR ligands such as TGFα [113] and activates the PI3K-AKT and MAPK pathways [114], in addition to also activating cyclin D1 expression [109]. On the contrary, PKC inhibition facilitates the differentiation of NSCs towards a neuronal phenotype, reducing their proliferation rate [115].…”

“…We hypothesize that the combination of these PKC targeting drugs with current treatments may enhance prognosis and survival time. Diterpenes with the capacity to individually regulate classical and novel PKC have recently been described for use in neuronal regeneration [113,114] and as putative treatments for other cancer types [111]. Thus, these agents could prove useful in the development of drugs either in standalone or in combined strategies with other compounds (e.g., PI3K inhibitors).…”

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

“…Among the 12-deoxyphorbol esters tested previously, , those with a phenylacetate or isobutyrate chain on C-13 (DPP and DPB, respectively) presented good activity at the lower range of tested concentrations. Therefore, it is reasonable to conceive that the nature of the biological activity of this class of compounds depends on the number and type of ester chains on the phorbol skeleton.…”

“…Particularly, it was found that the 12-deoxyphorbol isolated from Euphorbia resinifera, DPB, showed the highest capacity to stimulate neurogenesis in vivo . Furthermore, the long-term intranasal administration of DPB exerted not only a potent effect in stimulating neurogenesis in both the SVZ and DG, but the treatment of mice with this compound also improved their capacity to perform memory and learning tasks . The comparison of the activity of all 12-deoxyphorbols tested with DPB pointed at the role of the C-13 acyl chains as a key element in defining the potency of these compounds at activating PKC and promoting neurogenesis in vivo .…”

“…This neurotrophic factor stimulates the proliferation of undifferentiated NPC by binding and activating the epidermal growth factor receptor (EGFR). PKC-mediated phosphorylation of membrane-bound pro-TGFα facilitates the ADAM17-mediated shedding of the soluble TGFα ligand. − Furthermore, it has been recently described that DPB elicits TGFα release mimicking the effect of TGFα in cultures of NPC …”