pubmed.ncbi.nlm.nih.gov

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

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

Amy S Li et al. Engineering (Beijing). 2020 May.

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.

Keywords: Essential oil; Linalool; Monoterpenoid; Nicotinic acetylcholine receptor; γ-Aminobutyric acid type A receptor.

PubMed Disclaimer

Conflict of interest statement

Compliance with ethics guidelines Amy S. Li, Akimasa Iijima, Junhao Huang, Qing X. Li, and Yongli Chen declare that they have no conflicts of interest or financial conflicts to disclose.

Figures

Fig. 1.
Fig. 1.

Structures of (a) (−)-LL, (b) ME, (c) EG, and (d) citronellal.

Fig. 2.
Fig. 2.

Dose-dependent inhibition of LL on the whole-cell currents of the (a) α1β3γ2L GABAAR induced by 100 μmol·L−1 GABA and (b) α3β4 nAChR induced by 3 mmol·L−1 carbamoylcholine. Rat α1β3γ2L GABAAR was stably expressed in the WSS-1 cells, while the rat α3β4 nAChR subtype was stably expressed in the KXα3β4R2 cell line. The maximal inhibition by LL on the GABAAR was 44% of the control and 13% on the nAChR. Carbamoylcholine, a stable analog of acetylcholine, was used as a control for the whole-cell current recordings of the nAChR.

Fig. 3.
Fig. 3.

GABA dose–response curves in the absence (black) and presence (blue) of 5 mmol·L−1 LL in WSS-1 cells that expressed the rat α1β3γ2L GABAA receptor. The EC50 values were (36.2 ± 7.9) μmol·L−1 and (36.1 ± 23.8) μmol·L−1 in the absence and presence of LL, respectively. CGABA: the concentration of GABA.

Fig. 4.
Fig. 4.

(a) Significant increase in inhibition on rat α1β3γ2L GABAAR by the co-application of LL with PTZ relative to LL or PTZ alone. (b) Representative whole-cell current recording induced by 100 μmol·L−1 GABA (control, black), followed by 5 mmol·L−1 LL + 100 μmol·L−1 GABA (red) with subsequent return to the original control current with 100 μmol·L−1 GABA only (blue) 1 min after treatment.

Fig.5.
Fig.5.

Co-applications of 10 mmol·L−1 ME with 10 μmol·L−1 GABA and 100 μmol·L−1 GABA, respectively, weakly inhibited GABAAR functions. Co-applications of 10 mmol·L−1 EG with 10 μmol·L−1 GABA inhibited GABAAR functions. 5 mmol·L−1 (R)-C did not inhibit GABAAR-induced currents when co-applied with 40 μmol·L−1 GABA; and 5 mmol·L−1 (S)-C in the presence of 40 μmol·L−1 GABA weakly inhibited the GABAAR.

Similar articles

Cited by

References

    1. Jeon S, Hur J, Jeong HJ, Koo BS, Pak SC. SuHeXiang Wan essential oil alleviates amyloid beta induced memory impairment through inhibition of tau protein phosphorylation in mice. Am J Chin Med 2011;39(5):917–32. - PubMed
    1. Agra MF, Baracho GS, Nurit K, Basílio IJ, Coelho VP. Medicinal and poisonous diversity of the flora of “Cariri Paraibano”, Brazil. J Ethnopharmacol 2007;111 (2):383–95. - PubMed
    1. Lawless J. The encyclopedia of essential oils: the complete guide to the use of aromatic oils in aromatherapy, herbalism, health, and well being. San Francisco: Conari Press; 2013.
    1. Preedy VR, editor. Essential oils in food preservation, flavor and safety. Amsterdam: Academic Press; 2016.
    1. Chang CL, Cho IK, Li QX. Insecticidal activity of basil oil, trans-anethole, estragole, and linalool to adult fruit flies of Ceratitis capitata, Bactrocera dorsalis, and Bactrocera cucurbitae. J Econ Entomol 2009;102(1):203–9. - PubMed

LinkOut - more resources