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Abstract
Medicinal mushrooms of the genus Hericium are known to produce secondary metabolites with homeostatic properties for the central nervous system. We and others have recently demonstrated that among these metabolites cyathane diterpenoids and in particular erinacine C possess potent neurotrophin inducing properties in astrocytic cells. Yet, the signaling events downstream of erinacine C induced neurotrophin acitivity in neural-like adrenal phaeochromocytoma cells (PC12) cells have remained elusive. Similar, signaling events activated by erinacine C in astrocytic cells are unknown. Using a combination of genetic and pharmacological inhibitors we show that erinacine C induced neurotrophic activity mediates PC12 cell differentiation via the TrkA receptor and likely its associated PLCγ-, PI3K-, and MAPK/ERK pathways. Furthermore, a small library of transcriptional activation reporters revealed that erinacine C induces transcriptional activation mediated by DNA consensus binding sites of selected conserved transcription factor families. Among these, transcription is activated from an ETS consensus in a concentration dependent manner. Interestingly, induced ETS-consensus transcription occurs in parallel and independent of neurotrophin induction. This finding helps to explain the many pleiotropic functions of cyathane diterpenoids. Moreover, our studies provide genetic access to cyathane diterpenoid functions in astrocytic cells and help to mechanistically understand the action of cyathanes in glial cells.
Highlights
Medicinal mushrooms have been studied for neurotrophin inducing metabolites for about 25 years, and especially the genus Hericium has raised particular attention [1,2,3]
Using a combination of genetic and pharmacological inhibitors we show that erinacine C induced neurotrophic activity mediates PC12 cell differentiation via the Tropomyosin receptor kinase A (TrkA) receptor and likely its associated PLCγ, PI3K, and MAPK/ERK pathways
We have previously shown that erinacine C is able to induce the exBpiomreoslesciuolens 2o0f2B0,D10N, xF in 1321N1 cells, secreted Brain-Derived Neurotrophic Factor (BDNF) activity cannot be responsible for inducing P6Co1f219 differentiation as these cells lack expression of the corresponding BDNF receptor TrkB [23]
Summary
Medicinal mushrooms have been studied for neurotrophin inducing metabolites for about 25 years, and especially the genus Hericium has raised particular attention [1,2,3]. Extracts from both, basidomes and mycelial cultures of Hericium erinaceus are known to induce neurotrophin expression. We and others have recently revealed that isolated cyathane diterpenoids are able to mediate this neurotrophin-inducing activity of Hericium extracts [4,5,6,7,8]. Induction of neurotrophin expression by these cyathane diterpenoids does not occur in neuronal cells directly but in astrocytic cells. Among these compounds, erinacine C appeared interesting as this substance was able to induce both Nerve Growth Factor β (NGF) and Brain-Derived Neurotrophic Factor (BDNF) expression in the astrocytoma cell line 1321N1. The cascades downstream of neurotrophin induction by erinacine C that are likely mediated via the high-affinity Tropomyosin receptor kinase A (TrkA) in PC12 cells have not been identified so far
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