Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm.


METHODS
An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2-treated, and Src inhibitor damnacanthal-treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal.


CONCLUSIONS
The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.
Kusaka
Gen
G
Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Kimura
Hitoshi
H
Kusaka
Ikuyo
I
Perkins
Eddie
E
Nanda
Anil
A
Zhang
John H
JH
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000000981:diagnostic imaging; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D000880:Anthraquinones; D011743:Pyrimidines; C079170:damnacanthal; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases