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.