The acyl-glucuronide metabolite of ibuprofen has analgesic and anti-inflammatory effects via the TRPA1 channel

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Francesco De LoguRomina Nassini

Abstract

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation ...Continue Reading

Citations

Nov 2, 2019·Physiological Reviews·Karel TalaveraBernd Nilius
Dec 14, 2019·Behavioural Pharmacology·Merab G Tsagareli, Ivliane Nozadze
Aug 26, 2020·Expert Opinion on Therapeutic Targets·Daniel Souza Monteiro de AraujoFrancesco De Logu
Apr 4, 2021·International Journal of Molecular Sciences·Roberto MaglieFrancesco De Logu
Oct 17, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Cosmin I Ciotu, Michael J M Fischer

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