Putative Mode of Action of the Monoterpenoids Linalool, Methyl Eugenol, Estragole, and Citronellal on Ligand-Gated Ion Channels.

Abstract

Essential oil has been used as sedatives, anticonvulsants, and local anesthetics in traditional medical remedies; as preservatives for food, fruit, vegetable, and grain storage; and as bio-pesticides for food production. Linalool (LL), along with a few other major components such as methyl eugenol (ME), estragole (EG), and citronellal, are the active chemicals in many essential oils such as basil oil. Basil oil and the aforementioned monoterpenoids are potent against insect pests. However, the molecular mechanism of action of these chemical constituents is not well understood. It is well-known that the γ-aminobutyric acid type A receptors (GABAARs) and nicotinic acetylcholine receptor (nAChR) are primary molecular targets of the synthetic insecticides used in the market today. Furthermore, the GABAAR-targeted therapeutics have been used in clinics for many decades, including barbiturates and benzodiazepines, to name just a few. In this research, we studied the electrophysiological effects of LL, ME, EG, and citronellal on GABAAR and nAChR to further understand their versatility as therapeutic agents in traditional remedies and as insecticides. Our results revealed that LL inhibits both GABAAR and nAChR, which may explain its insecticidal activity. LL is a concentration-dependent, non-competitive inhibitor on GABAAR, as the half-maximal effective concentration (EC50) values of γ-aminobutyric acid (GABA) for the rat α1β3γ2L GABAAR were not affected by LL: (36.2 ± 7.9) μmol·L-1 and (36.1 ± 23.8) μmol·L-1 in the absence and presence of 5 mmol·L-1 LL, respectively. The half-maximal inhibitory concentration (IC50) of LL on GABAAR was approximately 3.2 mmol·L-1. Considering that multiple monoterpenoids are found within the same essential oil, it is likely that LL has a synergistic effect with ME, which has been previously characterized as both a GABAAR agonist and a positive allosteric modulator, and with other monoterpenoids, which offers a possible explanation for the sedative and anticonvulsant effects and the insecticidal activities of LL.