Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the hippocampal circuitry’s dentate gyrus (DG) integrate into 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 developing drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and the DG of mice, affecting neuroblasts differentiation and neuronal maturation. A concomitant improvement in learning and spatial memory task 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 this molecule’s role in developing pharmacological drugs to treat neurological and neuropsychiatric disorders associated with memory loss and deficient neurogenesis.

The generation of neurons from neural stem cells (NSC) is a complex process that occurs in mammals in brain regions referred to as neurogenic niches, mainly the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ). NSC -or radial glial-like cells in the DG- generate proliferative intermediate progenitors [1] in both niches, generating slow proliferating neuronal progenitors (neuroblasts), to a lesser extent, glial progenitors, which differentiate into astrocytes or oligodendrocytes. Neuroblasts differentiate into mature neurons. Whereas granule cell neurons generated within the DG integrate into hippocampal circuits, SVZ neuroblasts migrate toward the olfactory bulb, producing olfactory interneurons. DG neurogenesis has been linked to learning and memory and several different neurological and neuropsychiatric pathologies, such as depression and stress response. Alterations in the neurogenic rate and a reduction in the number of granule cells have been associated with depression and suicidal behavior, whereas antidepressants promote hippocampal neurogenesis in rodents. Neurogenesis is regulated by growth factors released within the niches, such as neuregulin or transforming growth factor-alpha (TGFα), which activate ErbB receptors within the DG and SVZ, promoting neurogenesis. Interestingly, behavioral alterations have been found in individuals with disrupted neuregulin signaling, and cognitive improvement has been observed in mouse models of ischemia upon treatment with TGFα. In this context, seeking agents that modulate growth factor release would help facilitate new neurons and contribute to circuit reformation and function recovery.

ErbB ligands such as amphiregulin or TGFα are released to the extracellular medium in a proteolytic reaction catalyzed by the A Disintegrin and Metalloproteinase (ADAM) family, such as ADAM17. This enzyme’s selectivity for each ligand is determined by phosphorylation reactions catalyzed by kinases of the protein kinase C (PKC) family. PKC consists of three subfamilies of kinases: the classical, the novel, and the atypical. Classical PKCα activated by phorbol-12-myristate-13-acetate (PMA) catalyzes the phosphorylation of TGFα and amphiregulin precursors that facilitate their shedding mediated by ADAM17 and releasing the soluble ligand outside the cell. Similarly, activation of novel PKCδ is required for ADAM17 mediated secretion of neuregulin. Overall, ADAM17 substrate specificity and selectivity are mediated by the activation of different PKC isozymes, thus playing a key role in the secretion of different types of growth factors.

Previous reports show that diterpene compounds with 12-deoxyphorbol structures isolated from plants of the Euphorbia genus, with a capacity to activate specific isozymes of PKC, promote neural proliferation progenitors three days after direct intracerebroventricular administration. The purpose of this work is to study the long-term effect of non-invasive administration of diterpenes on neurogenesis and cognitive performance and understand their mechanism of action.

In conclusion, we have found that intranasal treatment of mice with ER272 promotes neurogenesis and improves cognitive performance. This compound facilitates the release of growth factors that activate ErbB receptors such as neuregulin or TGFα, suggesting a role for ER272 as a possible drug to promote neurogenesis in diseases associated with cognitive impairment.

Ref: https://www.nature.com/articles/s41386-020-00934-y