Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury

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Abstract
The 21-aminosteroid lipid-peroxidation inhibitor, tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major tirilazad metabolite in animals and man, U-89678 is formed when the 4-5 double bond in the A-ring is reduced and has been postulated to contribute significantly to tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 microliters of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured cortex 3 hours post-SAH. The results revealed that 0.3 and 1.0 mg/kg tirilazad significantly reduced SAH-induced BBB damage 35.2% (p < 0.05) and 60.6% (p < 0.0001), respectively, in comparison to treatment with vehicle. The 0.3- and 1.0-mg/kg doses of U-89678 also decreased injury by 39.1% (p < 0.05) and 21.3% (not significant), respectively. In the second experiment, the investigators assessed the relative abilities of tirilazad and U-89678 to protect cultured neurons from iron-induced lipid peroxidative injury. Fetal mouse spinal cord cells were pretreated with 3, 10, or 30 microM tirilazad or U-89678 for 1 hour and then exposed to 200 microM ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [3H]alpha-(methyl)-aminoisobutyric acid 45 minutes after the FAS treatment. Both compounds enhanced neuronal survival in a concentration-dependent fashion. Although the two were equally efficacious, U-89678 was slightly more potent than its parent. On the basis of these findings, the authors conclude that the tirilazad metabolite, U-89678, possesses vaso- and neuroprotective properties that are essentially equivalent to the parent 21-aminosteroid. Hence, U-89678 probably contributes to the protective effects of tirilazad in SAH and other insults to the central nervous system.

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