Iridoid esters from Valeriana pavonii Poepp. & Endl. as GABAA modulators: Structural insights in their binding mode and structure-activity relationship

Context: Valeriana pavonii Poepp. & Endl. (Caprifoliaceae), is a plant used in traditional medicine as a tranquilizer in Colombia. Valerian extracts have been widely used since ancient times for their sedative and anxiolytic properties; however, the way its active metabolites, including iridoids, interact on their respective targets is not fully understood. Aims: To isolate and identificate active iridoid esters from V. pavonii. Perform in vitro inhibition assays and computational analyses to study their possible interaction on the benzodiazepine site of the GABAA receptor. Methods: Two compounds were obtained from dichloromethane and petroleum ether fractions of V. pavonii, respectively, by chromatographic techniques. The structural elucidation was performed by NMR and spectroscopic analyses. In vitro inhibition assays of the binding of 3H-flunitrazepam (3H-FNZ) for the benzodiazepine binding site of the GABAA receptor (BDZ-bs of the GABAA receptor) were carried out. Results: Two iridoid esters, hydrine-type valepotriates (compounds 1 and 2), were reported for the first time in V. pavonii. Both iridoids, 1 and 2, inhibited the binding of 3H-FNZ on the BDZ-bs of the GABAA receptor (40% at 300 µM). Docking studies and MMGBSA calculations revealed that these compounds exhibited molecular interactions with crucial residues of the benzodiazepine site, similar to those observed for drugs like flunitrazepam, diazepam, and flumazenil. Conclusions: These findings contribute to understanding the in vivo activity of extracts of Valeriana pavonni on the central nervous system, which showed promising effects, especially as anticonvulsants, sedative-hypnotics, and antidepressants, through the modulation of the GABAergic system by hydrine-type valepotriates and its derivatives

Antinociceptive effect of critoniella acuminata, physalis peruviana and salvia rubescens

Se evaluó el efecto antinociceptivo de extractos, fracciones y compuestos de Critoniella acuminata, Physalis peruviana y Salvia rubescens mediante los métodos de placa caliente, contorsiones abdominales inducidas por ácido acético y ensayo de la formalina. La fracción de Critoniella acuminata en dosis de 100 mg/kg p.o. presentó actividad antinociceptiva al aumentar el tiempo de reacción del animal ante la aplicación de un estímulo térmico (método de la placa caliente), mientras que la fracción de Physalis peruviana, en una dosis de 100 mg/kg p. o., ejerce un efecto antinociceptivo frente al dolor generado por estímulos químicos (dolor visceral agudo) al inhibir en un 40% las contorsiones abdominales inducidas por ácido acético y el número de lamidos durante la fase ii (dolor inflamatorio agudo) en el ensayo de formalina. Estos resultados sugieren que la ayapina y la fracción de Physalis peruviana estudiadas tienen actividad antinociceptiva, con posibles mecanismos de tipo opioide y aine, respectivamente.The antinociceptive effect of extracts, fractions and compounds of Critoniella acuminata, Physalis peruviana and Salvia rubescens were evaluated by the follow methods: Hot Plate test, acetic acid induced abdominal writhing and Formalin test. The fraction of Critoniella acuminata at doses of 100mg/kg p.o. exhibited antinociceptive effect in the hot plate test; while Physalis peruviana fraction at doses of 100 mg/kg p.o., showed an antinociceptive effect against the pain chemically induced. This fraction produced 40% inhibition of the acetic acid induced writhing (acute visceral nociception) and the licks during phase ii (acute inflammatory nociception) of the formalin test. The findings of this experimental study suggest that fractions of Critoniella acuminata and Physalis peruviana possess antinociceptive activity with opioid and nsaid-like mechanisms respectively

EFECTO DE NAPROXENO MICROENCAPSULADO EN MICROESFERAS DE ÁCIDO POLI (LÁCTICO-CO-GLICÓLICO) SOBRE EDEMA PLANTAR INDUCIDO POR CARRAGENINA EN RATAS EFFECT OF MICROENCAPSULATED NAPROXEN INTO POLY(LACTIDE-CO-GLYCOLIDE) MICROSPHERES ON CARRAGEENIN PAW EDEMA IN RATS

Las micropartículas son sistemas de entrega de fármacos ampliamente utilizados, que permiten mejorar la aplicabilidad terapéutica de fármacos tanto nuevos como convencionales. En el presente trabajo se elaboran micropartículas de un polímero biodegradable, ácido poli (láctico-co-glicólico), cargadas con naproxeno. Las mejores condiciones para la elaboración de las micropartículas son determinadas experimentalmente, encontrando que la relación fármaco: polímero, la cantidad de isopropanol, el volumen de fase acuosa, la velocidad de agitación y el tiempo de agitación influyen significativamente en las características de las micropartículas obtenidas. En el modelo de edema plantar inducido por carragenina en ratas Wistar, se encuentra que el naproxeno microencapsulado en dosis de 5 mg/Kg y 10 mg/Kg presenta mayor efecto antiinflamatorio que el naproxeno libre en dosis de 10 mg/Kg.ABSTRACT Microparticles are pharmaceutical dosage forms widely used because they may improve the therapeutic application of new and conventional drugs. In this work we make biodegradable microparticles with poly (lactic-co-glicolic) acid as polymer loaded with naproxen. The best microencapsulation conditions are experimentally determinate. We have found that the drug:polymer ratio, the isopropanol amount, the aqueous phase volume, the stir speed and the time of stir affect the microparticles characteristics. In the carragenin paw edema model, we have found that the microencapsulated naproxen at 5 mg/Kg and 10 mg/Kg showed greater effect than free naproxen at 10 mg/Kg

Valepotriate Hydrines Isolated from an Anticonvulsant Fraction of Valeriana pavonii Poepp. & Endl

The present study deals with the isolation and identification of three valepotriate hydrines that are first reported in Valeriana pavonii Poepp. & Endl. (Valerianaceae), which were obtained from a dichloromethane fraction showing anticonvulsant activity in vivo. The isolation and purification of dichloromethane fraction was carried out by chromatographic techniques. The compounds were identified by comparison of their 1H and 13C NMR spectra with previously published data in scientific literature. Maximal electroshock seizure was used as in vivo pharmacological test, additionally in vitro GABA-A/BDZ-binding site studies were performed. Three valepotriate hydrines: valtrate acetoxyhydrine (1), valtrate isovaleroyloxyhydrine (2) and valtrate chlorohydrine (3), were isolated from a dichloromethane fraction that offered 90% protection against crisis-like tonic-clonic seizures in an in vivo pharmacological maximal electroshock seizure (MES) test in mice (35 mg/kg, p.o.). According to an in vitro GABA-A/BDZ binding site test, the mechanism of action for these compounds does not involve binding to the GABA-A receptor. These compounds are reported in this species for the first time. The valepotriate hydrines isolated from V. pavonii could be active metabolites of this species with anticonvulsant properties, however further in vivo an in vitro studies are required. Their molecular mechanisms of action are unrelated to the benzodiazepine binding site of the GABA-A receptor.Fil: Giraldo, Sara E.. Universidad Nacional de Colombia; ColombiaFil: Rincón, Javier. Universidad Nacional de Colombia; ColombiaFil: Guerrero, Mario F.. Universidad Nacional de Colombia; ColombiaFil: López, Isabel. Universidad de la Laguna; EspañaFil: Jiménez, Ignacio. Universidad de la Laguna; EspañaFil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Wasowski, Cristina Lucia N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Vergel, Nadezdha E.. Universidad Nacional de Colombia; Colombi