Potent BACE1 inhibitory and neuroprotective activities of three lignans, styraxlignolide A, masutakeside I, and egonol, isolated from Styrax japonica.

Intracellular amyloid-β (Aβ) accumulation causes Alzheimer's disease (AD), and thus Aβ-related inhibitors, especially inhibitors of β-secretase 1, known as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) have been developed to treat AD. The purpose is to evaluate BACE1 inhibitory activity of the compounds isolated from Styrax japonica stem bark, traditionally used as herbal medicines. In this study, seven compounds were isolated, including three lignans, styraxlignolide A, masutakeside I, and egonol. Styraxlignolide A showed potent inhibitory activity against BACE1 with an IC50 value of 0.173 μM, followed by masutakeside I and egonol (IC50 = 0.376 and 1.509 μM, respectively), with mixed-type inhibition and low toxicity to normal MDCK and neuroblastoma SH-SY5Y cells. Furthermore, egonol, aglycone of masutakeside I, had neuroprotective activity in SH-SY5Y cells and Aβ42 aggregation inhibitory activity with blood-brain barrier permeability. The binding energies of styraxlignolide A, masutakeside I, and egonol, for BACE1 were predicted to be -11.753, -11.041, and - 8.413 kcal/mol, respectively. It was found that styraxlignolide A was the most potent BACE1 inhibitor compared with other herbal molecules reported to date. In conclusion, styraxlignolide A, masutakeside I, and egonol are potent mixed-type BACE1 inhibitors, suggesting that they can be used as drug candidates for therapeutic agents of AD.