ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. Fifteen flavonoids from Millettia brandisiana were evaluated for the multifunctional effect against AD pathogenesis, including butyrylcholine esterase (BuChE) inhibition, anti-amyloid beta (Aß) aggregation and neuroprotection against hydrogen peroxide (H2O2) toxicity in differentiated human neuroblastoma SH-SY5Y cell. To understand the mechanism and structure-activity relationship, binding interactions between flavonoids and the BuChE and Aß were investigated in silico. Furthermore, drug-likeness properties and ADMET parameters were evaluated in silico using SwissADME and pKCSM tools. All flavonoids exhibit a good drug-likeness profile. Six flavonoids have potency in BuChE inhibition, and four flavonoids show potency in anti-Aß aggregation. Flavonoids with the 6â³,6â³-dimethylchromeno- [2â³,3â³:7,8]-flavone structure show a favorable multifunctional effect. In silico analysis showed that flavonoids can bind in various positions to the catalytic triad, anionic site, and acyl pocket. In Aß1-42, potential flavonoids can attach to the central hydrophobic region and the C terminal hydrophobic and interfere with Aß interchain hydrogen binding. When compared together, it can inhibit multifunctional action with a favorable ADMET parameter and drug-likeness profile. In addition, candidine can prevent neuronal damage in differentiated SH-SY5Y neuroblastoma cells induced by H2O2 in a dose-dependent manner.
ABSTRACT
Marmin or 7-(6',7'-dihydroxygeranyl-oxy)coumarin is a compound isolated from Aegle marmelos Correa. In the study, we examined the effects of marmin on the contraction of guinea pig-isolated trachea stimulated by several inducers, namely histamine, metacholine, compound 48/80. We also evaluated its action against contraction induced by extracellular or intracellular calcium ion. The possibility of marmin to potentiate the relaxation effect of isoprenaline was also studied. Marmin added in the organ bath at 10 min prior to the agonist inhibited the contraction elicited by histamine and metacholine in a concentration-dependent manner. Moreover, marmin antagonized the histamine-induced contraction in competitive manner. Marmin mildly potentiated the relaxation effect of isoprenaline. In the study, marmin abrogated the contraction of tracheal smooth muscle induced by compound 48/80, an inducer of histamine release. Besides, marmin successfully inhibited CaCl(2)-induced contraction in Ca(2+)-free Krebs solution. Marmin also inhibited two phases of contraction which were consecutively induced by metacholine and CaCl(2) in Ca(2+)-free Krebs solution. Based on the results we concluded that marmin could inhibit contraction of the guinea-pig tracheal smooth muscle, especially by interfering histamine receptor, inhibiting the histamine release from mast, inhibiting intracellular Ca(2+) release from the intracellular store and the Ca(2+) influx through voltage-dependent Ca(2+) channels.
