Hericerin derivatives activates a pan‐neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory

• Published in: Journal of neurochemistry Vol. 165; no. 6; pp. 791 - 808
• Main Authors: Martínez‐Mármol, Ramón, Chai, YeJin, Conroy, Jacinta N., Khan, Zahra, Hong, Seong‐Min, Kim, Seon Beom, Gormal, Rachel S., Lee, Dae Hee, Lee, Jae Kang, Coulson, Elizabeth J., Lee, Mi Kyeong, Kim, Sun Yeou, Meunier, Frédéric A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2023; John Wiley and Sons Inc
• Subjects: Animals; Axonogenesis; BDNF; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Cells, Cultured; Cognitive ability; Convergence; Extracellular signal-regulated kinase; Growth factors; hericerin; Hericium erinaceus; Hippocampus; Hippocampus - metabolism; Hydrophobicity; Kinases; MAP Kinase Signaling System; Memory; Memory tasks; Mice; Mushrooms; Nerve growth factor; neurite outgrowth; Neurons; Neurons - metabolism; Original; ORIGINAL ARTICLES; Peripheral nerves; Receptor, trkB - metabolism; Regeneration; Signal Transduction; Signaling; Spatial analysis; Spatial Memory; TrkB; TrkB receptors; Tropomyosin; hericerin; TrkB; memory; neurite outgrowth; BDNF; Hericium erinaceus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15767

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N‐de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA‐12 only partly prevented the NDPIH‐induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK‐293T cells, an effect that was not sensitive to ANA‐12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan‐neurotrophic signaling pathway, leading to improved cognitive performance. We have purified biologically active compounds from the mushroom Hericium erinaceus. These molecules exert neurotrophic activity by promoting ERK1/2 signaling through a distinct but convergent pathway to BDNF/TrkB. NDPIH and hericene A produce extensive axon outgrowth and neurite branching of hippocampal neurons in vitro and enhanced memory performance in mice.