title: Citrus aurantium increases seizure latency to PTZ induced seizures in zebrafish thru NMDA and mGluR's I and II.
abstract: Epilepsy is a serious neurological condition and pharmacotherapy is not effective for all patients and causes serious adverse effects and pharmacokinetic and pharmacodynamic interactions. Natural products and ethnobotanical resources can help develop new therapeutic options for conditions like epilepsy. In Puerto Rico, ethnobotanical resources highlight the anxiolytic properties of a tea like preparation made from the leaves of the Citrus aurantium tree or bitter orange. Studies performed with essential oils from the peel of the fruit have shown to increase seizure latency to pentylenetetrazole (PTZ) and maximal electroshock seizure in mice. We characterized the extract composition, and used a model of PTZ induces seizures in the zebrafish and a receptor-ligand binding assay to determine if this preparation has anticonvulsant properties and its mechanism of action. We determined that the aqueous extract made from the leaves of the C. aurantium tree contains hesperidin, neohesperidin, and neohesperidin dihydrochalcone. Using our zebrafish model, we determined that exposure to the C. aurantium 28 mg/mL extract in aquarium water increases seizure latency by 119% compared to controls. We ruled out a mechanism involving GABAA receptors using the selective antagonist gabazine. We used two approaches to study the role of glutamate in the mechanism of the C. aurantium extract. The ligand binding assay revealed C. aurantium extracts at concentrations of 0.42 to 5.6 mg/mL significantly reduced [(3)H]Glu binding indicating an interaction with glutamate receptors, in particular with NMDA receptors and mGluR II. This interaction was confirmed with our animal model using selective receptor antagonists and we identified an interaction with mGluR I, not observed in the ligand binding experiment. These study provide evidence of the anticonvulsant properties of the aqueous extract made from the leaves of the C. aurantium tree and a mechanism involving NMDA and mGluR's I and II.
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Coral
authors.initials: C
authors.lastname: Rosa-Falero
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Torres-Rodríguez
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jordán
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Rígel
authors.initials: R
authors.lastname: Licier
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Yolimar
authors.initials: Y
authors.lastname: Santiago
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Zuleyma
authors.initials: Z
authors.lastname: Toledo
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Marely
authors.initials: M
authors.lastname: Santiago
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: Kiara
authors.initials: K
authors.lastname: Serrano
authors.affiliation: School of Science and Technology, Universidad del Este Carolina, PR, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosa
authors.affiliation: Neuropharmacology Laboratory, Pharmacology and Toxicology Department, University of Puerto Rico-Medical Sciences Campus San Juan, PR, USA.
authors.forename: José G
authors.initials: JG
authors.lastname: Ortiz
keywords: Citrus aurantium; Puerto Rican folklore; epilepsy; glutamate; natural products; zebrafish