Identification of embelin, a 3‐undecyl‐1,4‐benzoquinone from Embelia ribes as a multitargeted anti‐Alzheimer agent

Abstract

Beta-secreatse (BACE-1) and cholinesterases are clinically validated targets of Alzheimer's disease (AD), for which natural products have provided immense contribution.The multifaceted nature of AD signifies the need of multitargeted agents to tackle this disease. In the search of new natural products as dual BACE-1/cholinesterase inhibitors, a library of pure natural products was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE-1. The screening efforts have identified 1,4-benzoquinone "embelin," a natural product derived from Embelia ribes displaying inhibition of all three enzymes, with IC 50 values of 2.5, 5.4, and 2.1 μM, respectively. This screen has also identified isoquinoline alkaloids papaverine and L-tetrahydropalmatine as AChE inhibitors. Kinetic study has shown that embelin inhibits EeAChE and EqBChE with ki values of 4.59 and 0.57 μM, in an uncompetitive and noncompetitive manner, respectively. The interactions of embelin with allosteric peripheral anionic site of cholinesterases, has further supported the results of kinetic study. Embelin has also enhanced the activity of P-gp in LS-180 cells, the efflux pump which is involved in the clearance of amyloid-β from AD brain. Further, the cell viability study in neuronal cell line has indicated the excellent therapeutic window of embelin. These results are indicative of the fact that embelin is a multitargeted agent playing role in stopping the formation of amyloid-β oligomers (via inhibition of BACE-1), improves cholinergic-transmission (via inhibition of AChE/BChE) and increases amyloid-β clearance (via P-gp induction). K E Y W O R D Sacetylcholinesterase, Alzheimer's disease, BACE-1, butyrylcholinesterase, embelin, papaverine, L-tetrahydropalmatine

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

“…A fluorescence β-Secretase (BACE-1) Activity Detection Kit was purchased from Sigma–Aldrich and used to determine the effect of the synthesized flavone derivatives on β-secretase activity. The assay was carried out according to the manufacturer’s protocol as described earlier [ 47 , 48 ]. The enzyme solution was reacted with the substrate (7-methoxycumarin-4-acetyl-(Asn670, Lue671)-amyloid β/A4 precursor protein 770 fragment 667–676-(2,4-dinitrophenyl))Lys-Arg-Arg amide trifluoroacetate salt and sulfated polysaccharide samples in a fluorescence assay buffer in different wells.…”

Design of Curcumin and Flavonoid Derivatives with Acetylcholinesterase and Beta-Secretase Inhibitory Activities Using in Silico Approaches

“…All samples were assayed in triplicate, and bioactivity was reported with SEM. The method was as described earlier [ 80 , 81 ].…”

Embelin: A novel XIAP inhibitor for the prevention and treatment of chronic diseases

“…In vivo CCl₄ induced ↓LPO, AST, ALT, ALP, LDH, GGT; ↑SOD, CAT, GSH, GPX, GST [137] In vivo TAA ↑Survival, Liver fibrogenesis; ↓Necrosis, Apoptosis HICR [138] T A B L E 1 (Continued) In vivo IRIBI induced ↑La, HLT, GST; ↓BWL, LPO [140] In vivo ICV STZ induced ↓IL-1 β, IL-6, and TNF-α [141] In vivo PTZ induced ↓CCL2 mRNA, IL-1 mRNA, INF-γ mRNA [142] In vivo CUS induced ↓IL-6, TNF-α, IL-1β, COX-2, NO, TBARS [92] In vivo apomorphine induced ↓CI, SC, BDL, NA, SERT [143] In vivo CUS induced ↑BDNF, AO; ↓IL-6, TNF-α, IL-1β, COX-2 [92] In vivo SIA induced ↑RIMR, IR, BDNF, CREB1, SOD1, CAT [144] In vivo CCH induced ↓SMI, SPI; ↑BDNF, CREB1, APP, MAPT, SOD1, NF-κB mRNA [145] Alzheimer's disease in vitro SH-SY5Y ↓Cell viability, Cell proliferation [146] Obesity In vivo HFD induced ↓BW, BP, VFP, SLL, CAR, AGI TBARS ↑SOD, CAT, GSH [88] In vitro ST2, C3H10T1/2 ↓PPAR-γ, C/EBPs, aP2, Adipsin, SCD1, Dkk1, SREBPs, ACC-1, ↑nuclear translocation, TCF-4 [147] In vivo HFD induced ↓BW, Fat, SLT, FFA, TC, GTIR; ↓ALF, Dkk1 [147] Abbreviations: AA, ascorbic acid; AAA, abdominal aortic aneurysm; AADP, albumin anti-denaturation potential; AAI, acetic acid induced; AAIW, acetic acid induced writhing; ACC- high potential in the prevention and treatment of arthritis. For example, a study showed that embelin repressed inflammation and serum CTX-1 in collagen antibody-induced arthritis in mice, signifying its potential application in battling arthritis.…”

“…[141] Another study reported that embelin hampered the development of amyloid-β oligomers by downregulating β-secretase 1 (BACE-1); enhanced cholinergic-transmission by downregulation of acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) and upsurged amyloid-β clearance by P-gp activation. [146] Besides, a study reported neuroprotective and anti-Alzheimer's property of embelin in chronic cerebral hypoperfusion (CCH) model. In this model, administration of embelin markedly protected synaptic plasticity damage and enhanced expression of brainderived neurotrophic factor (BDNF), cAMP response element-binding protein1 (CREB1), amyloid precursor protein (APP), microtubuleassociated protein tau (MAPT), SOD1, and NF-κB mRNA levels triggered by chronic cerebral hypoperfusion rats.…”