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.
Highlights
Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor
A post-hoc analysis showed that scoparone at the doses of 2.5, 5 (p < 0.05), and 25 mg/kg (p < 0.01) significantly decreased the percentage of the time spent on the open arms as well as the percentage of open arm entries, indicating an anxiety-like behavior
Upon subchronic treatment, scoparone did not show any effect in the elevated plus-maze (EPM) at the doses 2.5, 5, 12.5, and 25 mg/kg (Supplementary Table S4)
Summary
Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. 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. We assessed the neuropharmacological effects of scoparone (Fig. 1) in a test battery of complex behavioral paradigms, including (a) depression-like behavior in the forced swim test (FST), Scientific Reports | (2022) 12:822. (b) anxiety-like behavior in the elevated plus-maze (EPM), and (c) learning and memory in the passive avoidance test (PA) after acute and subchronic, (i.p.) injections of scoparone (2.5–25 mg/kg) in Swiss albino mice. The PA paradigm was applied to assess scoparone’s procognitive/neuroprotective effects in both lipopolysaccharide (LPS) and scopolamine-induced mouse impaired learning and memory[13,14]
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