Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein

Abstract

Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57͞BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2°C below normal) with a dose of 300 mg͞kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E 2 concentrations in the brain. In cyclooxygenase (COX)-2 ؊/؊ mice, acetaminophen (300 mg͞kg) produced hypothermia accompanied by a reduction in brain PGE 2 levels, whereas in COX-1 ؊/؊ mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1 ؊/؊ mice had Ϸ70% lower levels of PGE2 than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE 2 levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE 2 that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.

Brain Tumor Oncolysis with Replication-Conditional Herpes Simplex Virus Type 1 Expressing the Prodrug-Activating Genes, CYP2B1 and Secreted Human Intestinal Carboxylesterase, in Combination with Cyclophosphamide and Irinotecan

“…We thus infected human Gli36DEGFR glioma cells with MGH2 and proceeded to harvest medium and cell extracts at different time points. Figure 4A and B shows that, between 20 and 120 hours after infection, there was a timedependent increase in SN-38 produced (reaching a maximum of 4.9 pmol/h/mg at 120 hours) and in carboxylesterase activity Approximately 4 hours after MGH2 infection, the temperature was raised to 39.8jC to block MGH2 replication (5,21,32). Five days later, the number of surviving cells was enumerated.…”

“…B, human U251 and T98G glioma cells were exposed to MGH2 at the indicated MOI and cyclophosphamide and CPT-11 at the indicated doses. Approximately 4 hours after MGH2 infection, the temperature was raised to 39.8jC to block MGH2 replication (5,21,32). Five days later, the number of surviving cells was enumerated.…”

Paracetamol: Update on its Analgesic Mechanism of Action

“…Altogether, these results indicate that the analgesic action of paracetamol cannot be attributed to inhibition of COX. Furthermore, the inhibitory effect of paracetamol on COX observed by some authors seems more closely related to its hypothermic/antipyretic effects than to its analgesic action [21,23].…”

“…Paracetamol seems to have only a weak inhibitory effect on prostaglandin production in cell culture, with IC 50 values mostly around 100 μM [20]. In animals, paracetamol reduced prostaglandin in cerebrospinal fluid [21], the spinal cord [22] and the brain [23,24]. Interestingly, AM404 was shown to be an inhibitor of COX on isolated COX-1 and COX-2 and in LPSinduced prostaglandin E 2 formation in RAW264.7 macrophages [2].…”

LASSBio‐881: an N‐acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation

“…The ability of LASSBio-881 to change body temperature was evaluated, according to Ayoub et al (2004). Adult Swiss mice, weighing between 18 and 25 g, were used in these experiments.…”