Ras protein contributes to cerebral vasospasm in a canine double-hemorrhage model.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) has been shown to be involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). In the present study we examined the role of Ras protein, an upstream regulator of MAPK, and the effects of the inhibitors of Ras farnesyltransferase (FTase), FTI-277 and FTase inhibitor I, on angiographic vasospasm and clinical evaluations.


METHODS
Twenty-five dogs were randomly divided into 5 groups: control, SAH, SAH+dimethyl sulfoxide, SAH+FTI-277, and SAH+FTase inhibitor I. An established canine double-hemorrhage model of SAH was used by injecting autologous arterial blood into the cisterna magna on days 0 and 2. Angiography was performed at days 0 and 7. Clinical behavior and the activation of Ras (GTP-Ras) and phosphorylated ERK1/2 of MAPK in the basilar arteries were examined.


RESULTS
Severe vasospasm was obtained in the SAH and SAH+dimethyl sulfoxide dogs (42.5+/-2.5% and 38.9+/-2.4%, respectively). Enhanced GTP-Ras and phosphorylated ERK1/2 were observed in the spastic basilar arteries (P<0.05). Inhibitors of Ras FTase decreased GTP-Ras and phosphorylated ERK1/2, attenuated angiographic vasospasm, and improved appetite and activity scores.


CONCLUSIONS
Ras contributes to cerebral vasospasm, and inhibitors of Ras FTase may have potential in the management of cerebral vasospasm.
Yamaguchi
Mitsuo
M
Department of Neurosurgery, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana 71130-3932, USA.
Zhou
Changman
C
Nanda
Anil
A
Zhang
John H
JH
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D023421:Models, Animal; D010766:Phosphorylation; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000473:pathology; D020301:Vasospasm, Intracranial / Q000378:metabolism* / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; C096856:FTI 277; D016166:Free Radical Scavengers; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D004121:Dimethyl Sulfoxide