Hericium erinaceus mycelium and its isolated erinacine A protection from MPTP-induced neurotoxicity through the ER stress, triggering an apoptosis cascade

Hericium erinaceus (Lion’s mane or Yamabushitake) is an edible mushroom with medicinal properties; it grows on old or dead broadleaf trees. It is used as a food and herbal medicine in Japan and China without harmful effects [1]. The mushroom may be a good candidate for inducing neuronal differentiation and promoting neuronal survival [2]. Both the mycelium (erinacines A-I) and the fruiting bodies (Hericenone C-H) are the source of many bioactive extracts with drug efficacy. Hericium erinaceus has been extensively documented and possesses a range of therapeutic properties, such as antioxidant activity [3], hypolipidemic activity [4], hemagglutinating activity [5], antimicrobial activity [6], antiaging activity [7], immune modulation and anticancer activities [8, 9]. Erinacine A has small molecular weight components that are the major active agents isolated from the cultured mycelium of H. erinaceus. These diterpenoid compounds also play a role in varied functions, including neuroprotection through nerve growth factor (NGF) synthesis [10]. Therefore, H. erinaceus is attracting attention as a novel resource, not only for medicinal drugs, but also for dietary phytochemicals for disease prevention and health promotion through use of its biological properties [11]. Our previous study focused on exploring the biological agent of erinacine A from H. erinaceus mycelium and its structural elucidation by ethanol extraction and HPLC analysis techniques [12, 13]. However, the mechanism by which H. erinaceus mycelium and its isolated diterpenoid derivative, erinacine A, promote neuron cell survival and protection from MPTP-induced neurotoxicity remains poorly understood, as does the mechanism by which H. erinaceus mycelium and erinacine A initiate neuroprotection against MPTP injury to the brain.

Parkinson’s disease (PD) involves a distinct sequence of events behind the selective neuronal death that occurs in PD, but these events are not fully understood [14–16]. Numerous diseases of the nervous system, such as Parkinson’s disease (PD) produce excessive free radical generation (reactive oxygen species [ROS] and reactive nitrogen species [RNS]), which then cause oxidative damage. These include lipids, oxidative S-nitrosylation proteins and nucleic acids, which have been linked to apoptosis by the high levels of ROS in dopamine neurons due to dopamine metabolism. Various disease models for PD also show the involvement of the drug 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) [17, 18]. Furthermore, the MPTP animal model is useful for the study of neurodegeneration in PD. The neurotoxic effects of MPTP are thought to be mediated by its metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and monoamine oxidase-B (MAO-B) in neuron cells, leading to a number of deleterious effects on cellular function, such as impairing the dopaminergic nigrostriatal neurons, generating free radicals from the mitochondria and a neuroinflammatory response, similar to those seen in PD [19, 20]. Our previous investigation focused on exploring the biological agent of erinacine A from H. erinaceus mycelium, its structural elucidation by ethanol extraction and HPLC analysis techniques [12, 13]. However, the mechanism by which H. erinaceus mycelium and its isolated diterpenoid derivative, erinacine A, are able to effectively improve the neuroprotective effects of the endoplasmic reticulum (ER) stress pathway and apoptosis, as well as how the signal cascades become activated, remain poorly understood.

Numerous studies have demonstrated that the ER stress pathway might be crucial in various CNS degenerative diseases [21]. In fact, ER stress may be related to neuronal death. In particular, the JNK/p38 MAPK/CHOP pathways involved in ER-stress-induced apoptosis in the neurons are implicated in PD [22]. In addition, energy metabolism with cultured neuronal cells, including dopaminergic neurons, showed that MPP + triggers ER stress and induces a number of genes [23]. Thus, extreme oxidant and peroxide levels from the neurotoxicity of MPTP suggest that inhibition of antioxidant defenses results in inflammatory effects and generation of ROS or RNS found in PD-related neuron damage [24, 25]. MPTP injury of the brain then induces oxidative stress, which leads to activate the multiple-cellular-signaling pathway, such as the IRE1? pathway. IRE1? binds TNF receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1) and downstream kinases that further activate Jun N-terminal kinase (JNK) and nuclear factor-?B (NF-?B), which has also been linked to PD [26, 27]. In the present study, we explore the biological agent of H. erinaceus mycelium that is associated with protection against ER stress and loss of dopaminergic nigrostriatal neurons.

In our previous study, we investigated the molecular mechanisms underlying H. erinaceus that inhibit global cerebral ischemic injury via inactivation of the iNOS/RNS and p38 MAPK/CHOP pathways, which may be among the possible pathways involved in stroke-related neuron injury [12, 13]. In the present study, we assess the neuroprotective effect of H. erinaceus mycelium and its isolated compound erinacine A, as well as its relevance to idiopathic PD in the MPTP mouse model. We were able to demonstrate that H. erinaceus mycelium, a known antioxidant, is able to protect against the endoplasmic reticulum stress induced by the loss of dopaminergic neurons and disordered motor function by MPTP injury. This results in its isolated compound erinacine A promoting neuronal cell survival due to MPP+ -mediated induction expression of Fas and Bax via IRE1?/TRAF2 complex formation and phosphorylation of the JNK1/2, p38 and NF-kB pathways. Moreover, developing more effective dietary H. erinaceus mycelium for PD is an important goal.