Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents

Essential oils were obtained by hydrodistillation of the umbels+seeds and stems of Ferula akitschkensis (FAEO_u/s and FAEO_stm, respectively) and analyzed by gas chromatography and gas chromatography-mass spectrometry. Fifty-two compounds were identified in FAEO_u/s; the primary components were sabinene, α-pinene, β-pinene, terpinen-4-ol, eremophilene, and 2-himachalen-7-ol, whereas the primary components of FAEO_stm were myristicin and geranylacetone. FAEO_u/s, β-pinene, sabinene, Î₃-terpinene, geranylacetone, isobornyl acetate, and (E)-2-nonenal stimulated [Ca²⁺]_i mobilization in human neutrophils, with the most potent being geranylacetone (EC₅₀ = 7.6 ± 1.9 μM) and isobornyl acetate 6.4 ± 1.7 (EC₅₀ = 7.6 ± 1.9 μM). In addition, treatment of neutrophils with β-pinene, sabinene, Î₃-terpinene, geranylacetone, and isobornyl acetate desensitized the cells to N-formyl-Met-Leu-Phe (fMLF)- and interleukin-8 (IL-8)-induced [Ca²⁺]_i flux and inhibited fMLF-induced chemotaxis. The effects of β-pinene, sabinene, Î₃-terpinene, geranylacetone, and isobornyl acetate on neutrophil [Ca²⁺]_i flux were inhibited by transient receptor potential (TRP) channel blockers. Furthermore, the most potent compound, geranylacetone, activated Ca²⁺ influx in TRPV1-transfected HEK293 cells. In contrast, myristicin inhibited neutrophil [Ca²⁺]_i flux stimulated by fMLF and IL-8 and inhibited capsaicin-induced Ca²⁺ influx in TRPV1-transfected HEK293 cells. These findings, as well as pharmacophore modeling of TRP agonists, suggest that geranylacetone is a TRPV1 agonist, whereas myristicin is a TRPV1 antagonist. Thus, at least part of the medicinal properties of Ferula essential oils may be due to modulatory effects on TRP channels.