Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot

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Abstract
The present study was undertaken to investigate the effect of U-74006F on malondialdehyde (a by-product of lipid peroxidation) in subarachnoid clot. Eighteen cynomolgus monkeys were divided into three groups of six each. There were two U-74006F-treated groups, receiving doses of 0.3 or 1.0 mg/kg, and a placebo-treated group. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and placement of subarachnoid clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after the experimental subarachnoid hemorrhage (SAH), angiography was repeated and the animals were killed. In the placebo-treated group, significant vasospasm occurred in the MCA on the side of the clot (p less than 0.01). After U-74006F treatment at both dosages, significantly less vasospasm developed in the clot-side MCA (p less than 0.01). The content of malondialdehyde was measured by both the thiobarbituric acid test and high-performance liquid chromatography (HPLC). Comparing the two methods, HPLC proved to be more accurate than the thiobarbituric acid test, especially for measurement of low concentrations of malondialdehyde. In the placebo-treated group, the malondialdehyde content was significantly increased in the Day 7 clot (p less than 0.05). In contrast, malondialdehyde content in freshly prepared clot was very low. In the 0.3-mg/kg U-74006F group, the malondialdehyde content of clot was significantly less at Day 7 compared to clot from the placebo-treated group (p less than 0.05). Although the malondialdehyde content of clot from the 1.0 mg/kg U-74006F-treated group was less than that of placebo, it was not significantly so. Malondialdehyde was not detected in the actual vessel wall of the MCA of any group. These results suggest that lipid peroxidation in subarachnoid clot may play a role in the pathogenesis of vasospasm and that the salutary effects of U-74006F in vasospasm may be mediated by a reduction of lipid peroxidation in SAH.