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

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.

Paracetamol – An old drug with new mechanisms of action

“…74 Therefore, a conclusion was formulated that a protein variant of COX-1, which also probably mediates the antipyretic effect of paracetamol in the hypothalamus is the target of paracetamol-induced hypothermia rather than COX-1. 69 In contrast, some research does not corroborate to the COXdependent central mechanism of paracetamol action. For instance, a combination of paracetamol with a COX inhibitor, eg ibuprofen, improves the analgesic effect and exhibits antipyretic activity, in contrast to the effect of both these compounds administered separately.…”

“…60 Subsequently, research conducted by Hinz and Brune Moreover, therapeutically administered paracetamol also reduced PGE 2 biosynthesis in the hypothalamus in wild-type fever mice with the COX-1 gene, but not in feverish COX-1 knockout mice. 69 Therefore, paracetamol-induced hypothermia is temporarily correlated with a decrease in PGE 2 synthesis in the brain. 70 Thus, it is known that the antipyretic effect of paracetamol depends on the inhibition of the enzyme derived from the COX-1 gene.…”

“…54 After COX-3 exclusion, there are two possible targets for paracetamol-induced hypothermia: either COX-1 or a COX-1 protein variant. 69 To check whether COX-1 is the target, a study with the use of a selective COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560) and a dual inhibitor indomethacin in normothermic mice was carried out. In both cases, hypothermia at pharmacologically active doses was not induced, 69 compared to cases where paracetamol caused hypothermia in feverish mice even at therapeutic doses, despite its antipyretic effects.…”

“…69 To check whether COX-1 is the target, a study with the use of a selective COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560) and a dual inhibitor indomethacin in normothermic mice was carried out. In both cases, hypothermia at pharmacologically active doses was not induced, 69 compared to cases where paracetamol caused hypothermia in feverish mice even at therapeutic doses, despite its antipyretic effects. 71 This hypothermic effect may have been mediated through AM404, 72,73 which is not certain, since the reduction of the conversion of paracetamol to AM404 by inhibition of fatty acid amido hydrolase (FAAH) did not prevent the development of hypothermia induced by paracetamol (Table 2).…”

“…61 Nevertheless, regarding the hypothermic and antipyretic effects of paracetamol, it seems highly likely that they are mediated by a centrally expressed protein variant of COX-1, as shown in recent studies. 69…”