Neuropsychopharmacological profiling of scoparone in mice

Abstract

Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal administration (2.5–25 mg/kg) in Swiss mice and determined its brain concentrations and its effects on the endocannabinoid system (ECS) and related lipids using LC–ESI–MS/MS. Scoparone showed no effect in the forced swimming test (FST) but, administered acutely, led to a bell-shaped anxiogenic-like behavior in the elevated plus-maze test and bell-shaped procognitive effects in the passive avoidance test when given subchronically and acutely. Scoparone rapidly but moderately accumulated in the brain (Cmax < 15 min) with an apparent first-order elimination (95% eliminated at 1 h). Acute scoparone administration (5 mg/kg) significantly increased brain arachidonic acid, prostaglandins, and N-acylethanolamines (NAEs) in the FST. Conversely, subchronic scoparone treatment (2.5 mg/kg) decreased NAEs and increased 2-arachidonoylglycerol. Scoparone differentially impacted ECS lipid remodeling in the brain independent of serine hydrolase modulation. Overall, the unexpectedly potent central effects of scoparone observed in mice could have toxicopharmacological implications for humans.

Coumarin derivatives against amyloid-beta 40 – 42 peptide and tau protein

“…Additionally, another furanocoumarin, imperatorin, with an isoamylenoxy group, was included, as such a long aliphatic chain may dramatically change the pharmacological functions, as proved in our previous studies [13]. The present project aimed to investigate Aβ40/42 and tau structure-dependent inhibiting properties of selected coumarin analogs and demonstrate the multitargeted character of these drugs in AD by way of the rapid screening method via the bacteria cell model of AD [14]. The above-mentioned screening method was used for the first time in this study to evaluate the coumarins' neuroprotective activities.…”

“…Escherichia coli (E. coli) competent cells -strain BL21 (DE3), were transformed with the pET28a vector (Novagen, Inc., Madison, WI, USA) carrying the DNA sequence of Aβ42, as described previously [14].…”

“…Thioflavin S (Th-S) fluorescence and absorbance were tracked using a DTX 800 plate reader Multimode Detector equipped with Multimode Analysis Software (Beckman-Coulter, USA) with filters of 430/35 and 485/20 nm for the excitation and emission wavelengths, respectively. The detection was done as described previously [14].…”

“…Aβ42 was provided from Bachem (Switzerland) and in vitro analysis was performed as described previously [14]. For aggregate-free preparation, Aβ42 (5 mg) was solubilized in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; 2 mL) under vigorous stirring, sonication aliquoting and HFIP evaporation, and stored at -33ºC.…”

“…The amyloid peak, at 485 nm, was used to evaluate and quantify the amyloid concentration. The applied parameters and procedures were described previously by Espargaró et al [14].…”