Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound (6) and one new natural product (2) together with five known compounds (1,3–5,7) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester (1) and a cyathane diterpenoid, erincine A (3), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3-promoted NGF-induced neurite outgrowth in PC12 cells.

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In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A–J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K–R (1–8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9–11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1–25 μM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein.

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Sarcodonin G, one of the cyathane diterpenoids isolated from the mushroom Sarcodon scabrosus, possesses pronounced neurotrophic activity but ambiguous mechanical understanding. In this work, sarcodonin G was chosen as a lead compound to prepare a series of 19- O-benzoyl derivatives by semisynthesis and their neuritogenic activities were evaluated. 6 and 15 (10 μM) were investigated with opposite effects in PC12 cells. 6 exhibited a superior activity to sarcodonin G by promoting NGF-induced neurite outgrowth, while 15 showed an inhibitory effect. Supportingly, 6 and 15 (20 μM) significantly induced and suppressed neurite extension in primary cultured rat cortical neurons, respectively. In mechanism, the two derivatives were revealed to influence NGF-induced neurite outgrowth in PC12 cells through the regulation of PKC-dependent and -independent ERK/CREB signaling as well as the upstream TrkA receptor phosphorylation. Furthermore, a possible pattern of interaction among NGF, 6/15 and TrkA was presented using molecular simulations. It revealed that 6/15 may contribute to the stabilization of the NGF-TrkAd5 complex by establishing several hydrophobic and hydrogen-bond interactions with NGF and TrkA, respectively. Taken together, 6 and 15 modulate PKC-dependent and -independent ERK/CREB signaling pathways possibly by influencing the binding affinity of NGF to the receptor TrkA, and finally regulate neurite outgrowth in PC12 cells.