Abstract
TRPA1 is activated by electrophilic compounds such as mustard oil (MO). Here, we demonstrate a bimodal sensitivity of TRPA1 to ligustilide (Lig), an electrophilic volatile dihydrophthalide of dietary and medicinal relevance. Lig is a potent TRPA1 activator and is also capable to induce a modest block of MO activated currents. Aromatization to dehydroligustilide (DH-Lig), as occurs during aging of its botanical sources, reversed this profile, enhancing TRPA1 inhibition and reducing activation. Mutation of the reactive cysteines in mouseTRPA1 (C622S, C642S, C666S) dramatically reduced activation by MO and significantly reduced that by Lig, but had an almost negligible effect on the action of DH-Lig, whose activation mechanism of TRPA1 is therefore largely independent from the alkylation of cysteine residues. Taken together, these observations show that the phthalide structural motif is a versatile platform to investigate the modulation of TRPA1 by small molecules, being tunable in terms of activation/inhibition profile and mechanism of interaction. Finally, the action of Lig on TRPA1 may contribute to the gustatory effects of celery, its major dietary source, and to the pharmacological action of important plants from the Chinese and native American traditional medicines.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Appendino G, Daddario N, Minassi A, De Petrocellis L, Di Marzo V (2005) The taming of capsaicin: reversal of the vanilloid activity of N-acylvanillamides by aromatic iodination. J Med Chem 48:4663–4669
Avonto C, Taglialatela-Scafati O, Pollastro F, Minassi A, Di Marzo V, De Petrocellis L, Appendino G (2011) An NMR spectroscopic method to identify and classify thiol-trapping agents: revival of Michael acceptors for drug discovery? Angew Chem Int Ed Engl 50:467–471
Beck JJ, Stermitz FR (1995) Addition of methyl thioglycolate and benzylamine to (Z)-ligustilide, a bioactive unsaturated lactone constituent of several herbal medicines. An improves synthesis of (Z)-ligustilide. J Nat Prod 58:1047–1055
Chan SS, Cheng TY, Lin G (2007) Relaxation effects of ligustilide and senkyunolide A, two main constituents of Ligusticum chuanxiong, in rat isolated aorta. J Ethnopharmacol 111:677–680
Dietz BM, Liu D, Hagos GK, Yao P, Schinkovitz A, Pro SM, Deng S, Farnsworth NR, Pauli GF, van Breemen RB, Bolton JL (2008) Angelica sinensis and its alkylphthalides induce the detoxification enzyme NAD(P)H: quinone oxidoreductase 1 by alkylating Keap1. Chem Res Toxicol 21:1939–1948
Du J, Yu Y, Ke Y, Wang C, Zhu L, Qian ZM (2007) Ligustilide attenuates pain behavior induced by acetic acid or formalin. J Ethnopharmacol 112:211–214
Gijbels MJM, Scheffer JJ, Svendsen AB (1982) Phthalides in the essential oil from roots of Levisticum officinale. Planta Med 44:207–211
Guo J, Duan J, Shang E, Tang Y, Qian D (2009) Determination of ligustilide in rat brain after nasal administration of essential oil from Rhizoma chuanxiong. Fitoterapia 80:168–172
Guo J, Shang E, Duang J, Tang Y, Qian D (2011) Determination of ligustilide in the brain of freely moving rats using microdialysis coupled with ultra performance liquid chromatography/mass spectrometry. Fitoterapia 82:441–445
Hinman A, Chuang H-H, Bautista DM, Julius D (2007) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci USA 103:19564–19568
Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B (2007) Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci 27:9874–9884
Li XR, Liang YZ, Guo FQ (2006) Analysis of volatile oil in Rhizoma ligustici chuanxiong-radix paeoniae rubra by gas chromatography-mass spectrometry and chemometric resolution. Acta Pharmacol Sin 27:491–498
Lu Q, Qiu TQ, Yang H (2006) Ligustilide inhibits vascular smooth muscle cells proliferation. Eur J Pharmacol 542:136–140
Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545
Mei QB, Tao JY, Cui B (1991) Advances in the pharmacological studies of radix Angelica sinensis (oliv) diels (Chinese danggui). Chin Med J (Engl) 104:776–781
Meyerhof W (2005) Elucidation of mammalian bitter taste. Rev Physiol Biochem Pharmacol 154:37–72
Nilius B, Prenen J, Owsianik G (2011) Irritating channels: the case of TRPA1. J Physiol 589:1543–1549
Peng C, Xie X, Wang L, Guo L, Hu T (2009) Pharmacodynamic action and mechanism of volatile oil from Rhizoma Ligustici chaunxiong Hort. on treating headache. Phytomedicine 16:23–34
Potashman MH, Dugganm ME (2009) Covalent modifiers: an orthogonal approach to drug discovery. J Med Chem 52:1231–1246
Schinkovitz A, Pro SM, Main M, Chen SN, Jaki BU, Lankin DC, Pauli GF (2008) Dynamic nature of the ligustilide complex. J Nat Prod 71:1604–1611
Shao M, Qu K, Liu K, Zhang Y, Zhang L, Lian Z, Chen T, Liu J, Wu A, Tang Y, Zhu H (2011) Effects of ligustilide on lipopolysaccharide-induced endotoxic shock in rabbits. Planta Med 77:809–816
Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829
Tang J, Zhang Y, Hartman TG, Rosen RT, Ho CT (1990) Free and glycosidically bond volatile compounds in fresh celery (Apium graveolens L.). J Agric Food Chem 38:1937–1940
Wang J, Du JR, Wang Y, Kuang X, Wang CY (2010) Z-Ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-kappab pathway in primary rat microglia. Acta Pharmacol Sin 31:791–797
Wu XM, Qian ZM, Zhu L, Du F, Yung WH, Gong Q, Ke Y (2011) Neuroprotective effect of ligustilide against ischemia-reperfusion injury via up-regulation of erythropoietin and down-regulation of RTP801. Br J Pharmacol, in press
Yan R, Ko NL, Li S-L, Tam YK, Lin G (2008) Pharmacokinetics and metabolism of ligustilide, a major bioactive component in Rhizoma chuanxiong, in the rat. Drug Metab Dispos 36:400–408
Zhang L, Du JR, Wang J, Yu DK, Chen YS, He Y, Wang CY (2009) Z-Ligustilide extracted from radix Angelica sinensis decreased platelet aggregation induced by adp ex vivo and arterio-venous shunt thrombosis in vivo in rats. Yakugaku Zasshi 129:855–859
Acknowledgements
We thank all members of the Leuven laboratory for helpful suggestions and criticisms. The tetracycline-inducible mouse TRPA1-expressing CHO cell line was kindly provided by A. Patapoutian (La Jolla, USA). This work was supported by grants from the Belgian Federal Government, the Flemish Government, the Onderzoeksraad KU Leuven (GOA 2004/07, F.W.O G.0172.03, Interuniversity Poles of Attraction Program, the Prime Minister’s Office IUAP Nr. 3P4/23), Excellentiefinanciering EF/95). JZ was supported by grants from the Natural Science Foundation of China (No. 30900619), 973 Program (No.2012CB517805) and the Chongqing Science & Technology Commission (No. CSTC2009BB5330).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Zhong, J., Pollastro, F., Prenen, J. et al. Ligustilide: a novel TRPA1 modulator. Pflugers Arch - Eur J Physiol 462, 841–849 (2011). https://doi.org/10.1007/s00424-011-1021-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-011-1021-7