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

Summary & key facts

Researchers isolated two compounds from the medicinal mushroom Hericium erinaceus—N-de phenylethyl isohericerin (NDPIH) and hericene A. In lab cultures, these compounds caused strong axon growth and more branching in hippocampal neurons even without serum. Tests showed they activate ERK1/2 signaling and do not act only through the TrkB (BDNF) receptor. In mice, feeding the mushroom extract or hericene A raised neurotrophin signaling and led to better hippocampus-dependent memory. The authors describe hericene A as working through a new pan‑neurotrophic pathway that converges on ERK1/2.

Key facts:

• Two active compounds were purified from Hericium erinaceus: N-de phenylethyl isohericerin (NDPIH) and hericene A.
• NDPIH and hericene A produced extensive axon outgrowth and increased neurite branching in cultured hippocampal neurons, even in the absence of serum.
• Pharmacological blockade of TrkB with ANA-12 only partly prevented the NDPIH-induced neurotrophic effects, which suggests the effect is not fully dependent on TrkB/BDNF signaling.
• NDPIH activated ERK1/2 signaling in HEK-293T cells that do not express TrkB, showing ERK1/2 activation can occur without TrkB.
• When TrkB was present, the ERK1/2 activation by NDPIH was not sensitive to ANA-12, indicating a TrkB-independent route to ERK1/2 as well as possible TrkB-linked effects.
• Mice fed H. erinaceus crude extract or hericene A had increased neurotrophin expression and downstream signaling, and showed significantly improved hippocampal memory in the study.

Abstract

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.

Topics

Fungal Biology and Applications Nerve injury and regeneration Pain Mechanisms and Treatments

Categories

Health Sciences Medicine Physiology

Tags

Biochemistry Biology Brain-derived neurotrophic factor Cell biology Chemistry Hericium erinaceus Hippocampal formation In vitro Nerve growth factor Neurite Neuroscience Neurotrophic factors Neurotrophin Organic chemistry Raw material Receptor Signal transduction Tropomyosin receptor kinase B