Neuroprotection by a central nervous system-type prostacyclin receptor ligand demonstrated in monkeys subjected to middle cerebral artery occlusion and reperfusion - A positron emission tomography study
Neuroprotection by a central nervous system-type prostacyclin receptor ligand demonstrated in monkeys subjected to middle cerebral artery occlusion and reperfusion - A positron emission tomography study
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DOI：
10.1161/01.str.0000245088.60282.22
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发表时间：
2006-11-01
期刊：
影响因子：
8.3
通讯作者：
Watanabe, Yasuyoshi
中科院分区：
文献类型：
--
作者：
Cui, Yilong;Takamatsu, Hiroyuki;Watanabe, Yasuyoshi
背景和目的-最近，我们发现前列环素（PGI（2））受体的一种新亚型在中枢神经系统（CNS）中表达，这种亚型在配体特异性方面明显不同于外周亚型。合成了（15 R）-16-m-tolyl-17，18，19，20-tetranorisocarbacyclin（15 R-TIC），并证明其是CNS型PGI（2）受体的特异性配体。以前，我们证明了15 R-TIC在沙土鼠短暂前脑缺血和大鼠永久性大脑中动脉闭塞（MCAO）期间具有体内神经保护作用。此外，该化合物显示出对原代培养的海马神经元具有抗凋亡作用，表明其对缺血性损伤的神经保护作用是通过直接作用于CNS型PGI（2）受体而发生的。在食蟹猴短暂MCAO再灌注3小时之前和之后长达18小时。在MCAO发作后5分钟内静脉注射15 R-TIC甲酯（50 μ g/kg，n =4）或其载体（10%Intralipos，n=4），并连续输注5小时（50 μ g/kg/h）。正电子发射断层扫描结果显示，15 R-TIC显著缩小感兴趣的“梗死”区体积，减轻脑氧代谢率和氧提取分数的降低，这些保护作用并不归因于改善脑循环。结论-这些结果表明，15 R-TIC通过直接作用于CNS型PGI（2）受体，对猴MCAO的局灶性脑缺血具有有效的神经保护作用。
Background and Purpose-Recently, we found that a novel subtype of prostacyclin (PGI(2)) receptor clearly distinct from the peripheral subtype in terms of ligand specificity is expressed in the central nervous system (CNS). (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) was synthesized and demonstrated to be a specific ligand for this CNS-type PGI(2) receptor. Previously, we demonstrated 15R-TIC to be neuroprotective in vivo during transient forebrain ischemia in gerbils and permanent middle cerebral artery occlusion (MCAO) in rats. Furthermore, this compound was shown to exert an anti-apoptotic effect on primary cultured hippocampal neurons, indicating its neuroprotective effect against ischemic insults occurs via direct action on CNS-type PGI(2) receptor.Methods-Local cerebral hemodynamics and oxygen metabolism were measured simultaneously by using positron emission tomography with the O-15 steady-state method, before and up to 18 hours after 3-hour transient MCAO reperfusion in cynomolgus monkeys. Methyl ester of 15R-TIC (50 mu g/kg, n=4) or its vehicle (10% Intralipos, n=4) was injected intravenously within 5 minutes after onset of MCAO and continuously infused for 5 hours (50 mu g/kg per hour).Results-Neuropathology showed that 15R-TIC significantly reduced cortical damage after 3-hour MCAO. Positron emission tomography results showed 15R-TIC significantly reduced the volume of "infarct" region of interest and attenuated the decrease in cerebral metabolic rate of oxygen and oxygen extraction fraction, and these protective effects were not attributable to improvement of cerebral circulation.Conclusions-These results suggest that 15R-TIC has a potent neuroprotective effect against focal cerebral ischemia in a monkey MCAO via its direct action on CNS-type PGI(2) receptors.