Mechanism of action of a new endogenous antipyretic

发热作为宿主防御反应的一个组成部分与提高生存率有关。目前的发热模型涉及热原细胞因子和随后由这些细胞因子诱导的前列腺素（pg），特别是PGE_2的刺激。经典解热药物的作用主要是由于抑制花生四烯酸级联的环氧合酶（COX），从而减少pg的产生。除了COX外，现在已知花生四烯酸级联的细胞色素P-450分支。细胞色素P-450的各种抑制剂增加大鼠和小鼠的发热，表明该酶可能参与内源性退热。雄性Wistar大鼠在麻醉状态下腹腔内植入遥测发射机监测体温。在一些实验中，除了遥测器外，还给大鼠植入了脑插管。为了确定细胞色素P-450代谢物在脑内的作用部位，将细胞色素P-450抑制剂（SKF-525A）…More微量注射到清醒雄性大鼠脑内的各个部位。SKF-525A在腹腔注射脂多糖前15分钟注射。mPOA、室旁核和第三脑室微量注射SKF-525A可增强lps诱导的发热，下丘脑背区、穹窿和网状核注射SKF-525A对发热无显著影响。其次，测试了细胞色素P-450代谢物环氧二碳三烯酸（EETs）的各种异构体对发烧的影响。在IL-1β注射前10分钟，用相同的套管将各eet微量注射到清醒大鼠的mPOA中。11、12-EET减热与载药组比较。5、6-、8、9-和14、15-EET对发热时间无明显退热作用。上述结果提示细胞色素P-450的解热作用部位在下丘脑前内侧，11,12 - eet可能是内源性解热原在下丘脑产生的候选内源性解热物质。少

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