In this post, eucalyptol and 1,8-cineole will be used interchangeably. The featured post illustrates the presence of “eucalyptol” in everyday products.
A human study 
PubChem’s summary of ecalyptol, aka 1,8-cineol, cites a non mechanistic study that suggested that eucalyptol could reduce airway inflammation in patients with COPD, chronic opbstructive pulmonary disease. The outcome measure was COPD exacerbation , or severe flareup, per day, These patients received 3x 200 = 600 mg 1,8-cineol per day.  Assuming each patient has 5 liters of blood and that eucalyptol sticks around in the blood at at steady rate, this could be about 125 mg per liter of blood. Eucalyptol has a molecular mass of 154 gmol-1 , this comes to 8×10-4 M or 0.8 mM, or maybe one third this number as a steady state value.. Worth (2009) hypothesized that eucalyptol, with its “mucolytic, bronchodilating and anti-inflammatory” effects, would be an effective adjunct to inhaled β-agonists, anticholinergics or corticosteroids, or oral theophylline.  Improvements, as measured by a respirometer, were unimpressive. Patient reported results were significant. Dyspnea is the feeling of not being able to breath.
Vital capacity is the volume of air that can be inhaled or exhaled. Forced vital capacity involves exhalation deep inhalation to maximum lung capacity. None of these functions were dramatically affected by eucalyptal. Many aspects of daily life were significantly improved by ecualyptal. 
Rat tracheal “rings” 
Intact and dissociated tracheal smooth muscle were used for muscle contraction and patch-clamp recordings, respectively. In experiments involving muscle contraction, 1,8-cineole potentiated contractions at low concentrations and relaxed contractions induced by isotonic K+ at high concentrations. AMTB (a TRPM8 channel blocker) reduced the potentiation induced by 1,8-cineole while indomethacin (a COX inhibitor) did not block this effect. In dissociated myocytes, 1,8-cineole partially blocked Ba2+ currents through VGCC in a concentration-dependent manner. 1,8-Cineole shifted the steady-state activation and inactivation curves to the left and also reduced the current decay time constant. In conclusion, 1,8-cineole has a dual effect on tracheal smooth muscle contraction resulting in a biphasic effect. Our data suggest that the potentiation effect is mediated by activation of TRPM8 channels and the relaxation effect is mediated by the blockage of L-type VGCC. An airway smooth muscle cell study showed half max Ba2+ inhibition at 1 mM 1,8-cinol.  The authors also noted a biphasic response due to activation of TRPM8 channels.  Recall that TRPM8 is the cold receptor. In a separate study using HEK293 cells expressing TRPM8, 1,8-cineol was found to open TRPM8 channels with an EC50 of 7.7±2.0 mM compared to canonical (-) menthol with and EC50 of 4.1±1.3 μM. 
The authors also performed patch clamping of myocytes that strengthened their conclusion that the L-type voltage gated calcium channel was involved. They speculated that ecalyptol/1,8-cineole might have been acting as a channel blocker.  Part of the use of the the COX inhibitor indomethacin came from a previous study in guinea trachea made sensitive with ovalbumin, which altered response to 1,8-cineole relaxation in the presence of KCl induced contraction. 
MLCP, myosin light chain phosphatase was not addressed in the trachea ring force transduction experiment shown in this post but was addressed in the patch clamping experiments.
TRPM8 studies 
The blockage of inflammatory responses by 1,8-cineole was observed in a TRPM8 knockout mouse model.  This post will not present these data and jump to the last in which the human, mouse, and rat TRPM8 channel was expressed in HEK293 cells, system that is frequently used to study ion channels. In these experiments, TRMP8 channel conductance was measured by a Ca2+ sensitive fluorescent dye loaded in the cells. 
Another Ca2+ sensitive fluorescent dye study showed less than dramatic eucalyptol/1,8-cineole gating of the mouse TRPM8 channel. The exciting thing about the Cacares study  is that the EC50 for the human isoform of TRPM8 is in the range of the does used in the Worth COPD clinical trial.  Were these positive patient reported results due to TRPM8 in airway smooth muscle cells, immune system cells, or some other system? Does eucalyptal also odulate the N- and P/Q-type voltage gated Ca2+ channels?
- Worth, H., Schacher, C., & Dethlefsen, U. (2009). Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: a placebo-controlled double-blind trial. Respiratory research, 10(1), 69. PMC free article
- Pereira-Gonçalves Á, Ferreira-da-Silva FW, de Holanda-Angelin-Alves CM, Cardoso-Teixeira AC, Coelho-de-Souza AN, Leal-Cardoso JH. 1,8-Cineole blocks voltage-gated L-type calcium channels in tracheal smooth muscle. Pflugers Arch. 2018 Dec;470(12):1803-1813.
- Nascimento NRF, Refosco RMDC, Vasconcelos ECF, Kerntopf MR, Santos CF, Batista FJA, De Sousa CM, Fonteles MC (2009) 1,8-Cineole induces relaxation in rat and guinea-pig airway smoothmuscle. J Pharm Pharmacol 61:361–366
- Caceres, A. I., Liu, B., Jabba, S. V., Achanta, S., Morris, J. B., & Jordt, S. E. (2017). Transient Receptor Potential Cation Channel Subfamily M Member 8 channels mediate the anti-inflammatory effects of eucalyptol. British journal of pharmacology, 174(9), 867–879. PMC free article
- Behrendt, H. J., Germann, T., Gillen, C., Hatt, H., & Jostock, R. (2004). Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. British journal of pharmacology, 141(4), 737–745. PMC free article
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