Inhibitory activities of major anthraquinones and other constituents from Cassia obtusifolia against β-secretase and cholinesterases.
BACKGROUND
Semen Cassiae has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Alzheimer's disease (AD) models.


OBJECTIVE
The basic goal of this study was to evaluate the anti-AD activities of C. obtusifolia and its major constituents. Previously, the extract of C. obtusifolia seeds, was reported to have memory enhancing properties and anti-AD activity to ameliorate amyloid β-induced synaptic dysfunction. However, the responsible components of C. obtusifolia seeds in an AD are currently still unknown. In this study, we investigated the inhibitory effects of C. obtusifolia and its constituents against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) enzyme activity.


METHODS
In vitro cholinesterase enzyme assays by using AChE, BChE, and BACE1 were performed. We also scrutinized the potentials of Cassiae semen active component as BACE1 inhibitors via enzyme kinetics and molecular docking simulation.


RESULTS
In vitro enzyme assays demonstrated that C. obtusifolia and its major constituents have promising inhibitory potential against AChE, BChE, and BACE1. All Cassiae semen constituents exhibited potent inhibitory activities against AChE and BACE1 with IC50 values of 6.29-109µg/mL and 0.94-190µg/mL, whereas alaternin, questin, and toralactone gentiobioside exhibited significant inhibitory activities against BChE with IC50 values of 113.10-137.74µg/mL. Kinetic study revealed that alaternin noncompetitively inhibited, whereas cassiaside and emodin showed mixed-type inhibition against BACE1. Furthermore, molecular docking simulation results demonstrated that hydroxyl group of alaternin and emodin tightly interacted with the active site residues of BACE1 and their relevant binding energies (-6.62 and -6.89kcal/mol), indicating a higher affinity and tighter binding capacity of these compounds for the active site of BACE1.


CONCLUSIONS
The findings of the present study suggest the potential of C. obtusifolia and its major constituents for use in the development of therapeutic or preventive agents for AD, especially through inhibition of AChE, BChE and BACE1 activities.
Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Hyun Ah
HA
Jung
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
Md Yousof
MY
Ali
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
Hee Jin
HJ
Jung
College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
Hyong Oh
HO
Jeong
College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
Hae Young
HY
Chung
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea. Electronic address: choijs@pknu.ac.kr.
Jae Sue
JS
Choi
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000880:Anthraquinones / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism; D002366:Cassia / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D000432:Methanol / Q000737:chemistry; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000302:isolation & purification / Q000494:pharmacology; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D010946:Plants, Medicinal; D011485:Protein Binding; D011753:Pyrones / Q000302:isolation & purification / Q000494:pharmacology; D012639:Seeds / Q000737:chemistry; D012997:Solvents / Q000737:chemistry
D000880:Anthraquinones; D002800:Cholinesterase Inhibitors; D006027:Glycosides; D009281:Naphthalenes; D010936:Plant Extracts; D011753:Pyrones; D012997:Solvents; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000432:Methanol
Anthraquinones; BACE1; Cassia obtusifolia; ChEs; Molecular docking