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Updated: Aug 10, 2026
A Low Mortality Rat Model to Assess Delayed Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage
Published on: January 17, 2013
Ras protein contributes to cerebral vasospasm in a canine double-hemorrhage model
Mitsuo Yamaguchi1, Changman Zhou, Anil Nanda
1Department of Neurosurgery, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana 71130-3932, USA.
Background And Purpose:
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.
Insights
Ras protein contributes to cerebral vasospasm after subarachnoid hemorrhage. Inhibitors of Ras farnesyltransferase (FTase) reduced vasospasm and improved clinical outcomes in a canine model.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Signaling
Background:
- Mitogen-activated protein kinase (MAPK) pathway implicated in cerebral vasospasm post-subarachnoid hemorrhage (SAH).
- Ras protein acts as an upstream regulator of MAPK signaling.
Purpose of the Study:
- Investigate the role of Ras protein in SAH-induced cerebral vasospasm.
- Evaluate the therapeutic potential of Ras farnesyltransferase (FTase) inhibitors (FTI-277 and FTase inhibitor I) in mitigating vasospasm.
Main Methods:
- Utilized a canine double-hemorrhage SAH model.
- Administered FTase inhibitors or vehicle control to SAH dogs.
- Assessed angiographic vasospasm, clinical behavior, and molecular markers (GTP-Ras, phosphorylated ERK1/2) in basilar arteries.
Main Results:
- SAH induced significant cerebral vasospasm and increased GTP-Ras and phosphorylated ERK1/2 levels.
- FTase inhibitors significantly reduced GTP-Ras and phosphorylated ERK1/2.
- Treatment with FTase inhibitors attenuated angiographic vasospasm and improved clinical scores.
Conclusions:
- Ras protein plays a critical role in the pathogenesis of cerebral vasospasm following SAH.
- Ras FTase inhibitors demonstrate potential as a therapeutic strategy for managing cerebral vasospasm.
