Abstract
Hericium erinaceus, a valuable pharmaceutical and edible mushroom, contains potent bioactive compounds such as H. erinaceus mycelium (HEM) and its derived ethanol extraction of erinacine A, which have been found to regulate physiological functions in our previous study. However, HEM or erinacine A with post-treatment regimens also shows effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, but its mechanisms remain unknown. By using annexin-V–fluorescein-isothiocyanate (FITC)/propidium iodide staining and a 2’,7’ –dichlorofluorescin diacetate (DCFDA) staining assay, the cell death, cell viability, and reactive oxygen species (ROS) of 1-methyl-4-phenylpyridinium (MMP+)-treated Neuro-2a (N2a) cells with or without erinacine A addition were measured, respectively. Furthermore, signaling molecules for regulating the p21/GADD45 cell death pathways and PAKalpha, p21 (RAC1) activated kinase 1 (PAK1) survival pathways were also detected in the cells treated with MPP+ and erinacine A by Western blots. In neurotoxic animal models of MPTP induction, the effects of HEM or erinacine A and its mechanism in vivo were determined by measuring the TH-positive cell numbers and the protein level of the substantia nigra through a brain histological examination. Our results demonstrated that post-treatment with erinacine A was capable of preventing the cytotoxicity of neuronal cells and the production of ROS in vitro and in vivo through the neuroprotective mechanism for erinacine A to rescue the neurotoxicity through the disruption of the IRE1α/TRAF2 interaction and the reduction of p21 and GADD45 expression. In addition, erinacine A treatment activated the conserved signaling pathways for neuronal survival via the phosphorylation of PAK1, AKT, LIM domain kinase 2 (LIMK2), extracellular signal-regulated kinases (ERK), and Cofilin. Similar changes in the signal molecules also were found in the substantia nigra of the MPTP, which caused TH+ neuron damage after being treated with erinacine A in the post-treatment regimens in a dose-dependent manner. Taken together, our data indicated a novel mechanism for post-treatment with erinacine A to protect from neurotoxicity through regulating neuronal survival and cell death pathways.
Highlights
Parkinson’s disease (PD), one of the most common adult-onset movement disorders worldwide [1], is frequently categorized as a leading cause of age-associated movement disorder
A have nerve-growth properties that allow them to aid in the prevention of ischemic injury and brain impairment in a mouse model that resembles PD to neurons in the central nervous systems of subjects undergoing excessive oxidative stress [17,25]
Our data revealed that erinacine A treatment could increase the survival pathways and reduce the apoptotic neurons induced by MPP+
Summary
Parkinson’s disease (PD), one of the most common adult-onset movement disorders worldwide [1], is frequently categorized as a leading cause of age-associated movement disorder. Death due to progressive nigrostriatal dopaminergic neurodegeneration, which arises from various environmental and genetic factors, usually results in the consequent loss of projection fibers in the striatum [2]. It is imperative to develop more effective drugs to treat the progression of Parkinson’s disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into animals in order to produce the neurotoxin 1-methyl-4-phenylpyridinium (MPP+ ), which, similar to PD, causes permanent symptoms of Parkinson’s disease by destroying dopaminergic neurons in the substantia nigra of the brain [4]. Following uptake by the synaptic dopamine reuptake system, the MPP+ is further concentrated by the electrical gradient of the inner membrane and slowly penetrates the hydrophobic reaction site on the NADH dehydrogenase.
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