Effects of mitogen-activated protein kinase inhibitors on cerebral vasospasm in a double-hemorrhage model in dogs.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) may be involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. This study was conducted to investigate the ability of the MAPK inhibitors PD-98059 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 24 kg, were divided randomly into four groups: control SAH (four dogs), vehicle- (dimethyl sulfoxide, six dogs), PD-98059- (six dogs), and U-0126-treated groups (six dogs). The double-hemorrhage model was created by an autologous blood injection into the cisterna magna on Days 0 and 2. An intracisternal injection of MAPK inhibitors was administered once per day on Days 3 through 6. Cerebral angiography was performed on Days 0 and 7 before the animals were killed. Western blot analysis was used to study the effects of hemorrhage and drug treatment on the MAPK immunoprecipitation. Severe vasospasm developed in the dogs in the control and vehicle-treated groups (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 developed mild vasospasm (18.9 +/- 6.2%). In the U-0126-treated group, severe vasospasm was observed despite treatment (39.6 +/- 6.4%). The PD-98059 but not the U-0126 abolished MAPK immunoprecipitation in the spastic BAs. However, treatment 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 MAPK inhibitors on vasospasm have been investigated in vivo. The authors demonstrate that MAPK may play a role in vasospasm and that PD-98059 is a potential candidate for the treatment of cerebral vasospasm.
Tibbs
R
R
Department of Neurosurgery, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Zubkov
A
A
Aoki
K
K
Meguro
T
T
Badr
A
A
Parent
A
A
Zhang
J
J
D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D002533:Cerebral Angiography / Q000187:drug effects*; D002536:Cerebral Arteries / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D005419:Flavonoids / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D013345:Subarachnoid Hemorrhage / Q000000981:diagnostic imaging* / Q000473:pathology; D014665:Vasodilator Agents / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging* / Q000473:pathology
D002070:Butadienes; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D014665:Vasodilator Agents; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one