Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

Article


Ayoub, S. and Flower, R. J. 2019. Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes. European Journal of Pharmacology.
AuthorsAyoub, S. and Flower, R. J.
Abstract

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E₂ (PGE₂) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE₂-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE₂ biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.

JournalEuropean Journal of Pharmacology
ISSN0014-2999
Year2019
PublisherElsevier
Accepted author manuscript
License
File Access Level
Anyone
Digital Object Identifier (DOI)doi:10.1016/j.ejphar.2019.172609
Web address (URL)https://doi.org/10.1016/j.ejphar.2019.172609
Publication dates
Online14 Aug 2019
Publication process dates
Accepted14 Aug 2019
Deposited13 Sep 2019
Copyright holder© 2019 Elsevier.
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