Effects of mitogen-activated protein kinase inhibitors on cerebral vasospasm in a double-hemorrhage model in dogs

Object. Mitogen-activated protein kinase (MAPK) may be involved in the path ogenesis of cerebral vasospasm after subarachnoid hemorrhage. This study wa s conducted to investigate the ability of the MAPK inhibitors PD98059 and U -0126 to reverse vasospasm in a double-hemorrhage model in dogs. Methods. Twenty-two adult mongrel dogs of either sex, each weighing 18 to 2 4 kg, were divided randomly into four groups: control SAH (four dogs), vehi cle- (dimethyl sulfoxide, six dogs), PD-98059- (six dogs), and U-0126-treat ed groups (six dogs). The double-hemorrhage model was created by an autolog ous blood injection into the cisterna magna on Days 0 and 2. An intracister nal injection of MARK inhibitors was administered once per day on Days 3 th rough 6. Cerebral angiography was performed on Days 0 and 7 before the anim als were killed. Western blot analysis was used to study the effects of hem orrhage and drug treatment on the MAPK immunoprecipitation. Severe vasospasm developed in the dogs in the control and vehicle-treated g roups (basilar artery [BA] diameter reduction 46.6 +/- 5.5% and 49.3 +/- 4. 6%, respectively). In the PD-98059-treated group, most of the dogs develope d mild vasospasm (18.9 +/- 6.2%). In the U-0126-treated group, severe vasos pasm was observed despite treatment (39.6 +/- 6.4%). The PD-98059 but not t he U-0126 abolished MAPK immunoprecipitation in the spastic BAs. However, t reatment with either PD-98059 or U-0126 improved the clinical scores of the dogs. Conclusions. The present study is the first in which the effects of MARK in hibitors on vasospasm have been investigated in vivo. The authors demonstra te that MARK may play a role in vasospasm and that PD-98059 is a potential candidate for the treatment of cerebral vasospasm.