Neuroprotective Effects of Hericium erinaceus Extract

Hericium erinaceus (H. erinaceus), also known as Monkey Head Mushroom or Lion's Mane Mushroom, is a dual-purpose mushroom belonging to the Hericiaceae family in the fungal order Hericiales. For centuries, H. erinaceus has been used as a medicinal treatment for gastrointestinal disorders, liver and kidney diseases, spleen disorders, and heart regulation. In the past decade, there has been growing interest in the potential uses of H. erinaceus in treating various neurological and cognitive disorders. Additionally, some believe that it may have neuroprotective effects. Research indicates that H. erinaceus exhibits various therapeutic effects, including antioxidant, anti-inflammatory, lipid-lowering, anticoagulant, antibacterial, blood sugar-lowering, anti-diabetic, and anti-cancer properties. Furthermore, H. erinaceus induces the synthesis of nerve growth factor (NGF), inhibits the cytotoxicity of β-amyloid (Aβ), and protects nerve cells from death caused by oxidative stress or endoplasmic reticulum stress.

Positive effects of H. erinaceus have been observed in animal models for treating cognitive disorders, Alzheimer's disease, ischemic stroke, Parkinson's disease, and age-related hearing loss. Encouraging results have also been obtained in the treatment of depression.

Hericium erinaceus Extract

• Erinacines

Erinacines are substances obtained from the mycelium and fruiting bodies of H. erinaceus, belonging to a group known as cyanthane glycosides, classified as terpenoids. These substances are active molecules capable of traversing the blood-brain barrier and triggering the expression of nerve growth factors in the brain. They consist of five, six, and seven-membered rings, and cyanthane glycosides have an additional xylose attached to the sugar moiety. Three primary bioactivities of erinacines have been recognized. Firstly, they exhibit the capacity to enhance NGF synthesis. Secondly, they possess antibiotic properties. Thirdly, they can activate κ-opioid receptors. Up to now, 19 distinct erinacines have been isolated, with 10 displaying neuroprotective effects, including the stimulation of NGF synthesis (erinacines A, B, C, E, F, and H) and the promotion of axon growth (T, U, V, and P).

Fig. 1 Chemical structures of Erinacines. (Szućko-Kociuba, 2023)

Erinacine A serves as a naturally occurring, low-molecular-weight inducer of NGF synthesis, proving effective in mouse models of age-related neurological diseases when administered orally. Certain erinacines (A and S) also demonstrate effects in reducing β-amyloid deposition and enhancing the expression of genes that encode insulin-degrading enzyme. Erinacine A is exclusively found in the fermented mycelium and is absent in the fruiting bodies of H. erinaceus. In animal models, Erinacine E has shown utility in the treatment of neuropathic pain.

• Hericenones

Numerous derivatives of hericenones (A, B, C, D, E, F, G, H, I, J) have been extracted from the fruiting bodies of H. erinaceus, representing phenolic compounds with diverse biological activities. H. erinaceus stands as the exclusive source of these valuable acids. Hericenones A and B demonstrate cytotoxic effects against HeLa cervical cancer cells. Hericenones C-E and H promote the synthesis of nerve growth factor (NGF) and the expression of the NGF gene by activating the protein kinase A signaling pathway. The effectiveness of individual ketones is contingent upon the length and presence of double bonds in the fatty acid chain. Among them, hericenone E, possessing two double bonds, exhibits the most robust stimulation of NGF.

3-hydroxyhericenone F has a protective effect against endoplasmic reticulum (ER) stress-induced cell apoptosis. ER stress-induced cell apoptosis is associated with neuronal apoptosis in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases.

• Polysaccharides

Polysaccharides in fungi are primarily found in the cell wall, constituting up to 20% of the total mass in fruiting bodies and mycelium. Polysaccharides isolated from H. erinaceus, such as xyloglucan, glucan, heteroxylan, and galactoxyloglucan, have anti-tumor properties. The isolated polysaccharides from H. erinaceus have various functions, including promoting neurogenesis, peripheral nerve regeneration, muscle regeneration after injury, as well as immunostimulation, anti-cancer, and cholesterol-lowering activities.

Neuroprotective Potential of Hericium erinaceus Components

Since the 1990s, several in vitro studies have demonstrated the stimulating effects of hericenones (C, D, E, H) and erincines (A-F, H) extracted from H. erinaceus on the synthesis of nerve growth factor (NGF). Erinacine A has neuroprotective and therapeutic effects on improving the pathological conditions and behavioral defects associated with Parkinson's disease (PD) and Alzheimer's disease (AD). In vitro and in vivo studies have shown that erinacine A can reduce MPTP-induced neurotoxicity by activating cell survival pathways such as PAK1, AKT, LIMK2, and MEK, and by reducing cell death pathways such as IRE1α, TRAF2, ASK1, GADD45, and p21.

Oxidative stress is a crucial component of the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. The core of these molecular mechanisms involves the accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to damage to lipids, proteins, and organelles, disruption of mitochondrial membranes, and cell apoptosis, ultimately resulting in neuronal death. The antioxidant activity of H. erinaceus is mainly attributed to the presence of polysaccharides (β-glucans) and terpenoids (hericenones, erinacines).

Research suggests that the therapeutic effects of erinacine A involve protection against endoplasmic reticulum (ER) stress, which is associated with increased neurotoxicity and neuronal apoptosis. The main mechanism of action involves the activation of the RE1α/TRAF2, JNK1/2, and p38 MAPK pathways, leading to the regulation of various factors such as CHOP, IKB-β, NF-κB, Fas, and Bax. These factors can influence the process of cell apoptosis and protect neuronal cells. The activation of the RE1α/TRAF2 pathway is related to the regulation of ER stress response and may play a role in protecting neurons from the effects of oxidative stress and other factors. The JNK1/2 and p38 MAPK pathways are also involved in the regulation of ER stress response, as well as the modulation of neuronal cell apoptosis and survival processes. The expression of CHOP may affect the process of cell apoptosis, while IKB-β and NF-κB may participate in the regulation of inflammation. The expression of Fas and Bax can influence the process of cell apoptosis through the activation of appropriate pathways. In summary, erinacine A acts on various signaling pathways, which may play a crucial role in protecting neuronal cells from the effects of factors such as endoplasmic reticulum stress. The protective effects of erinacine A may contribute to reducing neurotoxicity and cell apoptosis, which is of significant importance in the prevention and treatment of neurodegenerative diseases.

Reference

1. Izabela Szućko-Kociuba, et al., Neurotrophic and Neuroprotective Effects of Hericium erinaceus, Int. J. Mol. Sci. 2023, 24(21), 15960.