Mechanism of action of a new endogenous antipyretic

新型内源性退热药的作用机制

• 批准号: 11670068
• 负责人: NAKASHIMA Toshihiro
• 金额: $ 2.24万
• 依托单位: Kyoto Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670068/
• 关键词: Antipyresis; Fever; Arachidonic acid cascade; EET; EET

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

发烧作为宿主防御反应的一个组成部分，与提高存活率有关。目前的发热模型涉及致热细胞因子和随后由这些细胞因子诱导的前列腺素(PGs)的产生，特别是对PGE_2的刺激。经典解热药的作用主要归因于抑制花生四烯酸级联的环氧合酶(COX)，从而减少PGs的产生。除COX外，目前已知花生四烯酸的细胞色素P-450分支也有级联作用。细胞色素P-450的不同抑制剂可引起大鼠和小鼠发热，提示该酶可能参与内源性解热。雄性Wistar大鼠在麻醉下在腹腔内植入遥测发射器以监测体温。在一些实验中，除了遥测仪外，还给老鼠植入了脑插管。为了确定细胞色素P-450代谢产物在脑内的作用部位，细胞色素P-450抑制剂(SKF-525A)…清醒雄性大鼠脑内不同部位微量注射More。SKF-525A在内毒素注射前15分钟注射。在mPOA、室旁核和第三脑室微量注射SKF-525A可增强内毒素引起的发热，而向下丘脑背侧区、穹隆和下丘脑网状核注射SKF-525A则无明显作用。其次，研究了细胞色素P-450代谢产物环氧二十碳三烯酸(EETs)的不同异构体对发热的影响。清醒大鼠在注射IL-1β前10min，用相同的插管向mPOA内微量注射EET。11，12-EET与赋形剂治疗组相比有明显的退热作用。5，6-，8，9-和14，15-EET对发热时程无明显解热作用，提示细胞色素P-450的解热作用部位位于下丘脑前内侧部，11，12-EET可能是下丘脑内源性解热的候选物质。较少

项目成果

W.Matsunaga: "Microtuble-associated protein-2 in the hypothalamo --"Neuroscience. 88(4). 1289-1297 (1999)

W.Matsunaga：“下丘脑中的微管相关蛋白 2 -”神经科学。

W.MATSUNAGA, S.MIYATA, Y.HASHIMOTO, S.-H.LIN T.NAKASHIMA, T.KIYOHARA and T.MATSUMOTO: "Microtuble-associated protein-2 in the pypothalamo-neurohypophysial system : low-molecular-weight microtuble-associated protein-2 in pituitary astrocytes."Neuroscience.

W.MATSUNAGA、S.MIYATA、Y.HASHIMOTO、S.-H.LIN T.NAKASHIMA、T.KIYOHARA 和 T.MATSUMOTO：“前丘脑-神经垂体系统中的微管相关蛋白 2：低分子量微管

W.MATSUNAGA, S.MIYATA, A.TAKAMATA, H.BUNN, T.NAKASHIMA and T.KIYOHARA: "LPS-induced Fos expression in oxytocin and vasopressin neurons of the rat hypothalamus."Brain Res.. 858. 9-18 (2000)

W.MATSUNAGA、S.MIYATA、A.TAKAMATA、H.BUNN、T.NAKASHIMA 和 T.KIYOHARA：“LPS 诱导大鼠下丘脑催产素和加压素神经元中的 Fos 表达。”Brain Res.. 858. 9-18

W.Matsunaga : "LPS-induced Fos expression in oxytocin and vasopressin neurons of the rat hypothalamus"Brain Res. . 858. 9-18 (2000)

W.Matsunaga：“大鼠下丘脑催产素和加压素神经元中 LPS 诱导的 Fos 表达”Brain Res。

J.ICHIKAWA, k.FURUYA, S.MIYATA, T.NAKASHIMA and T.KIYOHARA: "EGF enhances Ca^<2+> mobilization and capacitative Ca^<2+> entry in mouse mammary epithelial cells."Cell Biochem. Funct.. 18. 215-225 (2000)

J.ICHIKAWA、k.FURUYA、S.MIYATA、T.NAKASHIMA 和 T.KIYOHARA：“EGF 增强小鼠乳腺上皮细胞中的 Ca^2 动员和电容性 Ca^2 进入。”Cell Biochem。