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

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 mu l 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 mu M tirilazad or U-89678 for 1 hour and then exposed to 200 mu M ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [H-3]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.