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 [3H]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.
Highlights
Epilepsy affects 50 million people worldwide (Meyer et al, 2010)
Using a model of PTZ induced seizures in zebrafish, we documented the anticonvulsant properties of this aqueous extract and established a possible mechanism involving N-methyl-D-aspartic acid (NMDA) and metabotropic glutamate receptors (mGluR)’s I and Group II of the metabotropic glutamate receptors (II). This is the first time and aqueous extract made from the leaves of the C. aurantium tree has been studied, giving insight to the pharmacological properties of a preparation commonly used by patients, in Puerto Rico
C. aurantium is extensively used as a dietary supplement for weight loss— efficacy has not been established
Summary
Epilepsy affects 50 million people worldwide (Meyer et al, 2010). It is a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures caused by abnormalAbbreviations: CA, Citrus aurantium; [3H]Glu, [3H]Glutamate; AMPA, Alpha-amino-3-hydroxy-5-methylisox-azole-4-propionic acid; BSA, Bovine serum albumin; CPPG, (RS)-α-Cyclopropyl-4-phosphonophenylglycine; DCG-IV, (2S,2 3R,3 R)-2-(2 ,3 -Dicarboxycyclopropyl)glycine; EGLU,(2S)a-Ethylglutamic acid; FW, Fluorowillardiine; iGluR, Ionotropic glutamte receptor; KA, Kainic acid; L-AP4, L-(+)-2-Amino-4-phosphonobutyric acid; LCCG-I, (2S,1 S,2 S)-2-(Carboxycyclopropyl)glycine; mGluR I, Group I of the metabotropic glutamate receptor (1,5); mGluR II, Group II of the metabotropic glutamate receptors (2,3); mGluR III, Group III of the metabotropic glutamate receptors (4,6,7,8); NMDA, N-methyl-D-aspartic acid; PHCCC, N-Phenyl-7(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide; PTZ, Pentylenetetrazole; QA, quisqualic acid: (2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) propanoic acid); D-AP5, D-(-)-2-Amino-5-phosphonopentanoic acid; NBQX, 2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; UBP 301, (αS)-α-Amino-3-[(4-carboxyphenyl)methyl]-3,4-dihydro-5-iodo-2,4-dioxo1(2H)-pyrimidinepropanoic acid; ACN, Acetonitrile; MeOH, Methanol; GBZ, gabazine.neuronal firing. Epilepsy affects 50 million people worldwide (Meyer et al, 2010) It is a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures caused by abnormal. AED’s have serious adverse effects including sedation and drowsiness, cognitive impairment, hirsutism, weight gain (Cramer et al, 2010), and complex pharmacokinetic and pharmacodynamic interactions with an extensive number of commonly used medications (Patsalos and Perucca, 2003). These issues highlight the need for new and better therapeutic agents to replace current available options or to improve their effects. This can be achieved using natural products and ethnobotanical resources to identify possible candidates for drug development
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