Ethnopharmacology of medicinal plants used in anxiety and epilepsy: Effects on gamma-aminobutyric acid (GABA) metabolism

This thesis examined the pharmacology of medicinal plants traditionally used in anxiety disorders and epilepsy, and their effects on gamma-aminobutyric acid (GABA) metabolism. The mechanism of action of anxiolytic and antiepileptic plants was investigated using in vitro assays which measured the activity of glutamic acid decarboxylase (GAD) and GABA transaminase (GABA-T), the two primary enzymes involved in GABA metabolism. The pharmacological activity of antiepileptic plants used by the Q'eqchi' Maya healers (Southern Belize) was also investigated. A total of 60 botanical extracts and 35 pure phytochemicals were tested for activity in either one or both of these enzyme systems.;Ethnopharmacological analysis of Q'eqchi' Maya antiepileptic plants led to the discovery of several active species that inhibited GABA-T activity. There was a significant positive correlation between percent enzyme inhibition and relative frequency of use by the healers. This suggests that there is a pharmacological basis behind the selection of plants used for epilepsy, and reinforces the link between modern and traditional science. The Piperaceae was the most highly represented family and phytochemical characterization of its most active species, Piper tuerckheimii C. DC. ex Donn. Sm. was performed for the first time. In addition, a novel mechanism of action (GABA-T inhibition) for the related species, black pepper ( Piper nigrum L.) and its secondary metabolite piperine was reported. Lastly, several natural and synthetic piperamide compounds were identified based on quantitative structure activity relationship (QSAR) analysis as potential lead molecules for further drug design and development.;A number of anxiolytic botanicals were identified to have actions on GABA metabolism. An extract of gotukola (Centella asiatica L.) stimulated total GAD activity from rat brain and its activity may be partly attributed to its secondary metabolite asiaticoside, which also stimulated the recombinant human GAD65 enzyme. An extract of lemon balm (Melissa officinalis L) inhibited GABA-T activity and bioassay-guided fractionation lead to the identification of rosmarinic, ursolic and oleanolic acids as active principles in this extract. Thus, these and several other botanicals are recommended for further research in the GABA system.