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，与生存率的提高有关。目前的发热模型涉及致热性细胞因子和随后由这些细胞因子诱导的前列腺素（PGs），特别是PGE_2的刺激。经典的解热剂的作用主要归因于抑制花生四烯酸级联反应的环氧合酶（考克斯）并随后减少PG的产生。除考克斯外，目前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antipyeresis.雄性Wistar大鼠腹腔植入遥测发射器，以监测麻醉下的体温。在一些实验中，除了遥测器外，大鼠还被植入脑套管。为了确定细胞色素P-450代谢物在脑中的作用部位，细胞色素P-450抑制剂（SKF-525 A） ...更多信息 在清醒的雄性大鼠脑内的不同部位进行显微注射。在腹腔内注射脂多糖之前15分钟注射SKF-525 A。mPOA、室旁核和第三脑室微量注射SKF-525 A可增强LPS引起的发热，而下丘脑背侧区、穹窿和网状核注射SKF-525 A对发热无明显影响。第二，研究了细胞色素P-450代谢产物环氧二十碳三烯酸（E3）的不同异构体对发热的影响。在注射IL-1β前10 min，用同一套管向清醒大鼠mPOA内微量注射E14。与赋形剂治疗组相比，11，12-EET减轻发热。5，6-，8，9-和14，15-EET对发热时程无明显的解热作用，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可能是内源性发热原在下丘脑产生的一种内源性解热剂。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