Differential inhibition by nimesulide of the early and late phases of intravenous- and intracerebroventricular-LPS-induced fever in guinea pigs.
Differential inhibition by nimesulide of the early and late phases of intravenous- and intracerebroventricular-LPS-induced fever in guinea pigs.
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尼美舒利对豚鼠静脉内和脑室内 LPS 诱导发热的早期和晚期的差异抑制。
DOI：
10.1159/000054289
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发表时间：
2001
影响因子：
2.4
通讯作者：
Blatteis,CM
中科院分区：
文献类型：
--
作者：
Steiner,AA;Li,S;Llanos-Q,J;Blatteis,CM
目的：研究结果表明，诱导型环氧化酶(COX)-2，而不是组成型COX-1，在腹腔热原给药后约1.5小时在清醒大鼠的大脑中上调，全身给药COX-2抑制剂可消除发热，COX-2缺陷小鼠对腹腔脂多糖（LPS）不产生发热反应，这强烈暗示了COX-2在发热反应中的介导作用。然而，COX-2的生物合成明显慢于静脉注射LPS引起的发热。因此，诱导COX-2似乎不太可能在这种发热反应的启动中发挥作用，但COX-1的作用尚未被明确排除；或者，COX-2的本构异构体可能具有这样的作用。因此，我们研究了非选择性COX抑制剂吲哚美辛、COX-1选择性抑制剂SC-560和COX-2选择性抑制剂尼美舒利对有意识豚鼠静脉注射LPS诱导的特特性双相热的影响；它的发病潜伏期约为10分钟。方法：在LPS前30 min注射抑制剂，以不同剂量和途径的组合；他们各自的车辆是控制方案。连续监测中心温度（Tc），在LPS给药前和给药后每隔2小时测量血浆和脑pge2水平。结果：腹腔注射10 mg kg-1吲哚美辛对两期静脉LPS（2µg kg-1）发热均有减弱作用，但前者较后者明显；50mg kg-1时完全抑制发热反应。腹腔注射SC-560 （5 mg kg-1）不影响静脉注射LPS（2µg kg-1）的发热反应。尼美舒利腹腔注射（0.3、1.0和3.0 mg kg-1）剂量依赖性减弱静脉内LPS（0.1和2µg kg-1）发热；双相运动的第二阶段受到的影响明显大于第一阶段。尼美舒利腹腔注射也能防止血浆和脑pge2水平升高。脑室内LPS （150 ng kg-1）引起单相发热，发病潜伏期长（~ 30分钟）；它只伴随着大脑中pge2的升高，这意味着发热性pge2是直接在大脑中产生的。然而，腹腔注射尼美舒利（3mg kg-1）完全消除了这种反应，表明尼美舒利穿过血脑屏障。0.3 mg kg-1尼美舒利脑室内注射LPS（2µg kg-1）后血浆pge2升高，并再次明显减弱第二次发热峰。结论：COX-1不参与静脉内LPS热的产生，COX-2在豚鼠静脉内LPS热的晚期比早期发挥更大的作用。本构性COX-2的参与是在早期阶段推断的。
Objectives:The findings that inducible cyclooxygenase (COX)-2, but not constitutive COX-1, is upregulated in the brain of conscious rats ∼1.5 h after intraperitoneal pyrogen administration, that the systemic administration of COX-2 inhibitors abolishes fever, and that COX-2-deficient mice do not develop fever in response to intraperitoneal lipopolysaccharide (LPS) have strongly implicated COX-2 in the mediation of the febrile response. However, the biosynthesis of COX-2 is significantly slower than the onset of the fever produced by intravenously injected LPS. It consequently seems improbable that inducible COX-2 could play a role in the initiation of this febrile response, but a role for COX-1 has not yet been categorically ruled out; or, alternatively, a constitutive isoform of COX-2 could have such a role. We have studied, therefore, the effects of the non-selective COX inhibitor indomethacin, the COX-1-selective inhibitor SC-560, and the COX-2-selective inhibitor nimesulide on the characteristically biphasic fever induced by intravenous LPS in conscious guinea pigs; it has an onset latency of ∼10 min.Methods:We injected the inhibitors 30 min before LPS, in various combinations of doses and routes; their respective vehicles were the control solutions. Core temperatures (Tc) were monitored continuously, and plasma and brain PGE2levels were measured before and at 2-hour intervals after LPS administration.Results:Intraperitoneal indomethacin at 10 mg kg–1attenuated both phases of intravenous LPS (2 µg kg–1) fever, but the first more so than the second; at 50 mg kg–1, it inhibited the febrile response completely. Intraperitoneal SC-560 (5 mg kg–1) did not affect the febrile response to intravenous LPS (2 µg kg–1). Intraperitoneal nimesulide (0.3, 1.0, and 3.0 mg kg–1) dose dependently attenuated intravenous LPS (0.1 and 2 µg kg–1) fever; the second phase of the biphasic Tcrise was affected significantly more than the first. Intraperitoneal nimesulide also prevented the associated rises in plasma and brain PGE2levels. Intracerebroventricular LPS (150 ng kg–1) evoked a monophasic fever with a long onset latency (∼30 min); it was accompanied by a rise in brain PGE2only, implying that the febrigenic PGE2was generated directly in the brain. This response, however, was completely abolished by intraperitoneal nimesulide (3 mg kg–1), indicating that nimesulide crosses the blood-brain barrier. Intracerebroventricular nimesulide at 0.3 mg kg–1prevented the rise in plasma PGE2after intravenous LPS (2 µg kg–1) and again attenuated the second febrile peak significantly more than the first.Conclusions:COX-1 is not involved in intravenous LPS fever production, and COX-2 appears to play a greater role in the late than in the early phase of intravenous LPS fever in guinea pigs. The involvement of a constitutive COX-2 is inferred in the early phase.
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DOI：
10.1073/pnas.82.4.1074
发表时间：
1985-01-01
影响因子：
11.1
作者：
TABOR, S;RICHARDSON, CC
通讯作者：
RICHARDSON, CC
布氏锥虫的过氧化氢代谢。
影响因子：
1.5
作者：
P. Penketh;R. Klein
通讯作者：
R. Klein
影响因子：
4.1
作者：
BOVERIS, A;SIES, H;STOPPANI, OM
通讯作者：
STOPPANI, OM
Crithidia fasciculata 中锥硫酮还原酶的纯化和表征，这是一种新发现的含二硫键黄素蛋白还原酶家族的成员。
影响因子：
2.9
作者：
Shames,SL;Fairlamb,AH;Cerami,A;Walsh,CT
通讯作者：
Walsh,CT
影响因子：
56.9
作者：
CRAIK, CS;LARGMAN, C;RUTTER, WJ
通讯作者：
RUTTER, WJ