| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1989: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
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
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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
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