Effects of tirilazad mesylate on vasospasm and phospholipid hydroperoxides in a primate model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE

Tirilazad mesylate has been used in the attempt to prevent cerebral vasospasm after subarachnoid hemorrhage (SAH), although the actual targets of this agent in vivo have thus far been controversial. Chemiluminescence/high-performance liquid chromatography provided a new method for direct measurements of phosphatidylcholine hydroperoxide (PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) in vivo and showed that phosphatidylcholine is the lipid class most susceptible to lipid peroxidation. In the present study we measured those levels in a primate model of SAH for determination of the effects of tirilazad on vasospasm.

METHODS

Fourteen Macaca monkeys of both sexes were randomly assigned into 2 groups: a tirilazad group receiving a dosage of 0.3 mg/kg and a placebo group receiving only the vehicle in which tirilazad was delivered. After the induction of experimental SAH around the right middle cerebral artery on day 0, tirilazad or vehicle was administered intravenously every 8 hours for 6 days. On day 7, the animals were killed after angiography and regional cerebral blood flow measurements were performed. The levels of PCOOH and PEOOH were measured in the clots, bilateral parietal cortices, right frontal cortex contact with clots, cerebellar hemispheres, bilateral middle cerebral arteries, and basilar arteries.

RESULTS

In the placebo group, a significant vasospasm occurred in the cerebral arteries on both sides, but most prominently on the right side. The degree of vasospasm in the cerebral arteries was significantly attenuated in the tirilazad group (P<0.005). There were no significant differences in regional cerebral blood flow, PCOOH, and PEOOH levels in the clots, cerebral cortices, and cerebellar hemispheres between the 2 groups. In contrast, the levels of PCOOH in the cerebral arteries were significantly higher in the placebo group than in the tirilazad group (P<0.025). It was remarkable that the tirilazad treatments eliminated PCOOH in any vascular territory after SAH.

CONCLUSIONS

PCOOH in the artery wall may be an important indicator for vasospasm, and the inhibition of PCOOH may explain the efficacy of tirilazad on vasospasm.