A mixture of quercetin 4′-O-rhamnoside and isoquercitrin from Tilia americana var. mexicana and its biotransformation products with antidepressant activity in mice

• Published in: Journal of ethnopharmacology 2021-03, Vol.267 (NA), p.113619, Article 113619
• Main Authors: Martínez-Hernández, Gabriela Belen, Jiménez-Ferrer, Enrique, Román-Ramos, Rubén, Zamilpa, Alejandro, González-Cortazar, Manasés, León-Rivera, Ismael, Vargas-Villa, Gabriela, Herrera-Ruiz, Maribel
• Format: Article
• Language: English
• Subjects: 5-HT; Animals; Antidepressive Agents - isolation & purification; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Biotransformation; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Depression; Depression - metabolism; Depression - physiopathology; Depression - prevention & control; Depression - psychology; Disease Models, Animal; DOPAC; Exploratory Behavior - drug effects; Isoquercitrin; Male; Mice; Mice, Inbred ICR; Motor Activity - drug effects; p-HPAA; Phloroglucinol; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Quercetin - analogs & derivatives; Quercetin - isolation & purification; Quercetin - metabolism; Quercetin - pharmacology; Quercetin 4′-O-Rhamnoside; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT2A - metabolism; Serotonergic Neurons - drug effects; Serotonergic Neurons - metabolism; Serotonin - metabolism; Tilia - chemistry; Tilia americana
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2020.113619

The aerial parts of Tilia americana var. mexicana (Malvaceae, formerly Tiliaceae) or “sirimo” are used in Mexican traditional medicine for the relief of mild symptoms of mental stress, commonly referred to as "nerve diseases". Individuals use this plant to fall asleep, to calm states of nervous excitement, headaches, mood disorders, and general discomfort. Recent studies indicated that fractions standardized in their flavonoid content possess antidepressant activity in behavioral assays in mice. The present study aims to focus on the evaluation of the antidepressant effect of the mixture of two flavonoids (FMix), and its interaction with serotonergic drugs. Also, the pharmacological effect of the products of the metabolism of aglycone, quercetin, was evaluated in mice subjected to forced swimming test (FST) and open field test (OFT). A methanol-soluble extract obtained from leaves of Tilia americana was fractionated in an open column chromatographic separation. One of the fractions contained FMix wich is constituted of the mixture of quercetin 4′-O-rhamnoside (1, 47%) y isoquercitrin (2, 53%). The mice were divided into the several following groups: FMix (0.01, 0.1, 0.5, 1.0, and 2 mg/kg); FMix (1.0 mg/kg) and agonist DOI (2.0 mg/kg); FMix (1.0 mg/kg) and antagonist ketanserin (KET, 0.03 mg/kg) of 5-HT2A receptors; FMix (1.0 mg/kg) and selective agonist 8-OH-DPAT (8-OH, 0.01 mg/kg); FMix (1.0 mg/kg) and antagonist WAY100635 (WAY, 0.5 mg/kg) of 5HT1 receptors; Phloroglucinol (PHL); 3,4-dihydroxy-phenyl acid (DOPAC); p-hydroxyphenyl acetic acid (p-HPAA); and m-hydroxyphenyl acetic acid (m-HPAA) were tested in FST or OFT. FMix induced dependent-dose antidepressant activity and, at the highest dose administered, a sedative effect was also observed. The 8-OH-DPAT, or the DOI, or the KET combination with FMix (1.0 mg/kg) induced a higher antidepressant effect than compounds alone; there was no effect exerted with WAY. The activity on OFT increased only with the FMix and KET combination. At the same time, the products of the aglycone metabolism of quercetin, that is, DOPAC and p-HPAA, decreased the immobility time of the mice in FST at 1.0 mg/kg, and a dose-curve was formed for these. The antidepressant effect of FMix could depend, at least in part, on the degradation products of quercetin and with a possible action mode through interaction with the serotoninergic system. [Display omitted]