Participation of Arachiclonic Acid Lipoxygenase Products in the Pathogenesis of Cerebral Vasospasm After SAH.

花生四烯酸脂氧合酶产物参与 SAH 后脑血管痉挛的发病机制。

• 批准号: 01570813
• 负责人: WATANABE Takashi
• 金额: $ 1.22万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570813/
• 关键词: Subarachnoid Hemorrhage; Cerebral Vasospasm; Arachidonic Acid; Lipoxygenase; 12-HPETE; 12-HETE; 12-HPETE; 12-HETE

In our previously studies, cerebral vasospasm was experimentally produced by the canine two-hemorrhage model. 12-Lipoxygenase metabolites of the arachidonic acid, 12-hydroxyeicosatetraenoic acid (HETE), was mainly detected as a amount of about 2 nmol/ g wet weight in the subarachnoid clot by reversed-phase High-Performance Liquid chromatography (HPLC). This arachidonate 12-lipoxygenase metabolite was presumably formed rightly after blood clotting in the subarachnoid space by 12-lipoxygenase originated from platelets and leukocytes. We also investigated 5-lipoxygenase activity of basilar arteries with vasospasm in the same model. Twenty to one hundred fold of 5-HETE was produced in the vessels with vasospasm, compared with untreated ones. Moreover, leukotriene B_4 and C_4 were detected in the spasm arteries, but not in the control ones. This activation of 5-lipoxygenase pathway in the spasm arteries was due to the intrinsic 5-lipoxygenase of the vessels, which was stimulated by 12-Hydro … More peroxyeicosatetraenoic acid (HPETE), the precursor of 12-HETE, since leukocytes (rich sources of 5-lipoxygenase) were rarely found in the microscopic observation. These results led us to carry out the experiment to see whether the cisternal injection of 12-HPETE could cause the delayed cerebral vasospasm or not.12-HPETE and 12-HETE were synthesized from arachidonic acid by partially purified porcine leukocyte 12-lipoxygenase, and purified using straight-phase HPLC. The injection of 12-HPETE (0.5 mg) into the canine cisterna magna caused a delayed onset of cerebral vasospasm that lasted long. 12-HPETE in CSF was rapidly reduced to 12-HETE, which was also disappeared within 6 hours after cisternal injection. And then, intrathecal arteries began to contract. This contraction continued for 5 or 6 days. This phenomenon mimicked the cerebral vasospasm as shown in the one-hemorrhage model in our previous experiment. 12-HETE (0.5 mg) injected into CNS had much less potency to induce cerebral vasospasm. We substantiated that 12-HETE was contained in the subarachnoid clot. 12-HPETE is a possible initiator of the delayed cerebral vasospasm. Furthermore, the cisternal injection of 15-HPETE and 13-hydroperoxyoctadecadienoic acid (hydroperoxide of linoleic acid) also successfully caused delayed cerebral vasospasm. Lipid peroxides should be convincing candidates for the initiators of that. Less

在我们之前的研究中，通过犬两次出血模型实验产生了脑血管痉挛，花生四烯酸的12-脂氧合酶代谢物12-羟基二十碳四烯酸（HETE）在体内的含量主要为约2nmol/g湿重。通过反相高效液相色谱 (HPLC) 检测蛛网膜下腔凝块。 12-脂氧合酶代谢物可能是在来自血小板和白细胞的12-脂氧合酶在蛛网膜下腔血液凝固后立即形成的。我们还在同一模型中研究了血管痉挛的基底动脉的5-脂氧合酶活性的20至100倍。与未治疗的血管相比，血管痉挛的血管中产生了HETE，而且白三烯B_4和白三烯B_4也产生了。在痉挛动脉中检测到了 C_4，但在对照动脉中未检测到。痉挛动脉中 5-脂氧合酶途径的激活是由于血管内在的 5-脂氧合酶受到 12-氢过氧二十碳四烯酸的刺激（ HPETE），12-HETE 的前体，因为在显微镜下很少发现白细胞（5-脂氧合酶的丰富来源）这些结果促使我们进行了实验，看看脑池注射12-HPETE是否会引起迟发性脑血管痉挛。12-HPETE和12-HETE是由部分纯化的猪白细胞12-脂氧合酶从花生四烯酸合成的。 ，并使用直相 HPLC 进行纯化。将 12-HPETE (0.5 mg) 注射到犬小脑延髓池中会导致延迟。脑脊液中持续较长时间的脑血管痉挛迅速减少为12-HETE，在脑池注射后6小时内也消失，然后，这种收缩持续5或6天。这种现象模仿了我们之前的实验中注射 12-HETE（0.5 毫克）的单次出血模型中的脑血管痉挛。我们证实蛛网膜下腔凝块中含有 12-HETE，可能是迟发性脑血管痉挛的引发剂。此外，脑池注射 15-HPETE 和 13-氢过氧十八二烯酸。亚油酸的氢过氧化物）也成功地引起了迟发性脑血管痉挛。过氧化物应该是令人信服的引发剂候选者。

项目成果

Watanabe T, Asano T, Shimizu T.: "Neurochemical Correlates of Cerebral Ischemia" Bazan NG. Plenum Publishing Corporation, New York.,

Watanabe T、Asano T、Shimizu T.：“脑缺血的神经化学相关性”Bazan NG。

Watanabe T, Nishiyama M.: "Cerebral Ischemia and Lipoxygenase" Gendai Iryo. 121 (11). 79 - 82 (1989)

Watanabe T、Nishiyama M.：“脑缺血和脂氧合酶”Gendai Iryo。

Nishiyama M, Watanabe T.: "Lipoxygenase Metabolites and Neurotransmission" Experimental Medicine. 9 (1). 43 - 49 (1991)

Nishiyama M，Watanabe T.：“脂氧合酶代谢物和神经传递”实验医学。

渡辺 高志,西山 誠: "脳虚血とリポキシゲナ-ゼ" 現代医療. 21. 79-82 (1989)

Takashi Watanabe、Makoto Nishiyama：“脑缺血和脂氧合酶”现代医学 21. 79-82 (1989)。

渡辺高志,西山誠: "脳循環障害" 日本臨床. 6. (1990)

Takashi Watanabe、Makoto Nishiyama：“脑循环障碍”日本临床实践 6。（1990 年）