Mechanism of action of a new endogenous antipyretic

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Fever as a component of a host-defense response is associated with enhanced survival. The current model of fever involves pyrogenic cytokines and the subsequent induction of prostaglandins (PGs) by these cytokines, particularly stimulation of PGE_2. The action of classic antipyretic agents is primarily attributed to the inhibition of cyclooxygenase (COX) of arachidonic acid cascade and subsequently reduced generation of PGs. In addition to COX, it is now known that cytochrome P-450 branch of arachidonic acid cascade. Various inhibitors of cytochrome P-450 augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis.Male Wistar rats were implanted with telemetry transmitters in the abdominal cavity to monitor body temperature under anesthesia. In some experiments, rats were implanted with brain cannulas in addition to the telemeters. To determine the site of action of cytochrome P-450 metabolites in the brain, cytochrome P-450 inhibitor (SKF-525A) … More was microinjected into the various site of brain in conscious male rats. SKF-525A was injected 15 min prior to intraperitoneal injection of lipopolysaccharide. Microinjections of SKF-525A into the mPOA, paraventricular nucleus and 3rd ventricle enhanced the LPS-induced fever, while injections into dorsal hypothalamic area, fornix and reticular hypothalamic nucleus showed no remarkable effect on the fever. Second, various isomers of epoxyeicosatrienoic acids (EETs), metabolites of cytochrome P-450, were tested influence on fever. Each EETs were microinjected into the mPOA in conscious rats, 10 min before IL-1β injection using same cannula. 11, 12-EET attenuated fever compared with vehicle treated group. 5, 6-, 8, 9- and 14, 15-EET had no significant antipyretic effect on the time course of fever.These results suggest that the site of antipyretic action of cytochrome P-450 is antero-medial part of the hypothalamus, and that 11, 12-EET is a candidate of endogenous antipyretic which may be produced in the hypothalamus by endogenous pyrogens. Less