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

Summary & key facts

Researchers purified two new active compounds from the medicinal mushroom Hericium erinaceus and tested them on brain cells and mice. In lab-grown hippocampal neurons, the compounds—called NDPIH and hericene A—caused strong axon growth and branching even when growth support was removed. Tests showed NDPIH turns on a cell-signaling route called ERK1/2, and this happens even when the usual BDNF receptor (called TrkB) is not involved. Mice given the mushroom extract or hericene A had higher levels of growth-promoting proteins in the brain and showed better hippocampus-based memory. These results suggest the mushroom makes molecules that boost neuron growth and memory in cells and mice, but they were not tested in people yet.

Key facts:

• The team isolated two active compounds from Hericium erinaceus: N-de phenylethyl isohericerin (NDPIH) and a related compound called hericene A.
• Both compounds strongly promoted axon growth and branching in cultured hippocampal neurons, even when the cells had no serum (a common source of growth support).
• Blocking the BDNF receptor TrkB partly reduced NDPIH’s effects, which suggests some involvement of BDNF signaling but not the whole story.
• NDPIH activated ERK1/2, a downstream growth-signaling pathway, even in cells that lacked TrkB, showing NDPIH can use a different route that still converges on ERK1/2.
• Mice fed Hericium erinaceus extract or hericene A showed increased expression of neurotrophins (proteins that help neurons survive and grow) and had better hippocampal memory in behavioral tests.
• The findings show a 'pan-neurotrophic' effect—meaning the compound can boost multiple growth pathways that meet at ERK1/2—but the work was done in cells and mice, not in humans.

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