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. 2017 May 12:8:219.
doi: 10.3389/fphar.2017.00219. eCollection 2017.

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Chen Diling  1 , Yong Tianqiao  1 , Yang Jian  1 , Zheng Chaoqun  1   2 , Shuai Ou  1 , Xie Yizhen  1
Affiliations

Docking Studies and Biological Evaluation of a Potential β-Secretase Inhibitor of 3-Hydroxyhericenone F from Hericium erinaceus

Chen Diling et al. Front Pharmacol. .

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting approximately more than 5% of the population worldwide over the age 65, annually. The incidence of AD is expected to be higher in the next 10 years. AD patients experience poor prognosis and as a consequence new drugs and therapeutic strategies are required in order to improve the clinical responses and outcomes of AD. The purpose of the present study was to screen a certain number of potential compounds from herbal sources and investigate their corresponding mode of action. In the present study, the learning and memory effects of ethanol:water (8:2) extracts from Hericium erinaceus were evaluated on a dementia rat model. The model was established by intraperitoneal injection of 100 mg/kg/d D-galactose in rats. The results indicated that the extracts can significantly ameliorate the learning and memory abilities. Specific active ingredients were screened in vivo assays and the results were combined with molecular docking studies. Potential receptor-ligand interactions on the BACE1-inhibitor namely, 3-Hydroxyhericenone F (3HF) were investigated. The isolation of a limited amount of 3HF from the fruit body of H. erinaceus by chemical separation was conducted, and the mode of action of this compound was verified in NaN3-induced PC12 cells. The cell-based assays demonstrated that 3HF can significantly down-regulate the expression of BACE1 (p < 0.01), while additional AD intracellular markers namely, p-Tau and Aβ1-42 were further down-regulated (p < 0.05). The data further indicate that 3HF can ameliorate certain mitochondrial dysfunction conditions by the reversal of the decreasing level of mitochondrial respiratory chain complexes, the calcium ion levels ([Ca2+]), the inhibiton in the production of ROS, the increase in the mitochondrial membrane potential and ATP levels, and the regulation of the expression levels of the genes encoding for the p21, COX I, COX II, PARP1, and NF-κB proteins. The observations suggest the use of H. erinaceus in traditional medicine for the treatment of various neurological diseases and render 3HF as a promising naturally occurring chemical constituent for the treatment of AD via the inhibition of the β-secretase enzyme.

Keywords: 3-Hydroxyhericenone F; Alzheimer’s disease; Hericium erinaceus; active pharmaceutical ingredient; functional foods; molecular docking; regulatory mechanism.

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Figures

FIGURE 1
FIGURE 1
Effects of ethanol:water (8:2) extracts from Hericium erinaceus (EH) on D-galactose-induced deficit in rats. (A) Body weight changes during the treatment; (B,C) water maze tests results at the specified incubation periods and swimming times in NW; (D) spatial probe test results; (E) swimming trajectory during the spatial probe test; (F) cytokine levels of GM-CSF, TNF-γ, 1L-10, IL-2, 1L-17α, 1L-6, TNF-α, and VGEF-α in serum; (G,H) routine blood index changes. Control group (oral distilled water), model group [intraperitoneal injection (i.p) of 100 mg/kg/d D-galactose], low-dose group (concomitant administration by i.p injection of 100 mg/kg/d D-galactose and gavage at a dose of 50 mg/[kg⋅d] ethanol:water (8:2) extracts from H. erinaceus (EH)), high-dose group (concomitant administration by i.p injection of 100 mg/kg/d D-galactose and gavage at a dose of 50 mg/[kg⋅d] ethanol:water (8:2) extracts from H. erinaceus (EH)). Values are expressed as mean ± SD, #p < 0.05 vs. control group, ∗p < 0.05, ∗∗p < 0.01 vs. model group, indicates significant differences compared with the model group.
FIGURE 2
FIGURE 2
Histopathological changes and immunohistochemistry staining of Tau and Aβ42 in the brain tissues of D-galactose- induced deficit rats. (A) is the hematoxylin-eosin (HE) staining of hippocampal and thalamus, brain stem and cerebellum, midbrain nigra; (B) is HE staining of hippocampal, immunohistochemistry staining of the expression of Aβ42 and Tau protein in hippocampal.
FIGURE 3
FIGURE 3
Binding pattern of H. erinaceus compounds: (A-a) crystal structure of BACE1; (A-b) binding modes and co-crystal ligand in BACE1; (B) docking scores of compounds from H. erinaceus and co-crystal ligand (ZPX394); (C) intra and intermolecular hydrogen bonds; (D-a) crystal structure of BACE1 and (D-b) 3-Hydroxyhericenone F-mediated hydrogen bond interactions with Lys321 and Thr72 (green line).
FIGURE 4
FIGURE 4
Effects of 3HF on the mRNA expression levels of PARP1, p21, NF-κB p65, COX I, and COX II (A–E) and the expression of the proteins related to mitochondrial dysfunction. 3HF reduced BACE1 although it reduced p-Tau and Aβ42 expression (F,G). Cells were pretreated with 3HF at the concentrations of 0.05, 1.00, and 1.50 μg/ml for 2 h, followed by exposure to 0.03 mM of NaN3 for 12 h, and the protein extracts were used for Western blot analysis of the indicated proteins. The blots were probed with β-actin for the loading control validation #p < 0.01 compared with control group; ∗p < 0.05 and ∗∗p < 0.01 compared with the NaN3-treated group.
FIGURE 5
FIGURE 5
(A) is the extraction flowchart and chemical structure of 3HF. Effects of 3HF and NaN3 on PC12 cells (B–D) and effect of 3HF on ROS (E), [Ca2+]i (F), mitochondrial membrane potential (G), F(1)F(0)-ATPase (H), NADH-CoQ (I,J), COX I (K), COX II (L), NF-κB (M), Caspase-3 (N), and Caspase-9 (O) in NaN3-induced cytotoxicity PC12 cells. The cells were pretreated with 3HF at the concentrations of 0.05, 1.00 and 1.50 μg/ml for 2 h, followed by exposure to 0.03 mM of NaN3 for 24 h, whereas the control group was treated with PBS. Values are provided as the mean ± SD (n = 5) and % of the control group, #p < 0.01 compared with control group; ∗p < 0.05 and ∗∗p < 0.01 compared with the NaN3-treated group, indicates significant differences compared with the model group.
FIGURE 6
FIGURE 6
Effect of 3HF on the cellular and mitochondrial morphology. (A) The investigation was conducted by inverted microscope; (B) The investigation was conducted by fluorescent microscope at the wavelength of 490 nm. The number of cells and fluorescence intensity of the model group (treated with 0.03 mM NaN3 for 24 h) were lower compared with the control, while the 3HF increased the number of cells and fluorescence intensity; (C) The analysis was carried out by electron microscopy (1 and 5K). The 0.03 mM NaN3 treated groups indicated an ultrastructural change with disappearance of the nucleolus, condensed chromatin that was localized to the inner side of an intact nuclear membrane, blur mitochondria with disintegration and substantial lysis of cristae in PC12 cells.
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