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Inhibitory effect with antisense mitogen-activated protein kinase oligodeoxynucleotide against cerebral vasospasm in
Motoyoshi Satoh1, Andrew D Parent, John H Zhang
1Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Miss 39216, USA.
Background And Purpose:
Mitogen-activated protein kinase (MAPK) may be associated with the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study aimed to clarify the role of MAPK expression and activation during cerebral vasospasm and to evaluate the therapeutic effect on cerebral vasospasm using an antisense MAPK oligodeoxynucleotide (ODN).
Methods:
Antisense MAPK, sense MAPK, or scrambled ODN was injected into the rats intracisternally. We used a single-hemorrhage experimental SAH model to assess vasospasm in the basilar arteries at 30 minutes, 1 day, and 2 days after SAH by cross-sectional area measurement and other histological parameters. Immunohistochemistry and Western blot analysis were used to quantify MAPK expression and activation. In addition, a double-hemorrhage rat SAH model was used to test the effect of post-SAH treatment with antisense MAPK ODN.
Results:
Antisense MAPK therapy significantly inhibited cerebral vasospasm when compared with sense MAPK or scrambled ODN treatment on day 2. The immunohistochemistry and Western blotting performed in the basilar artery of rats that received antisense MAPK ODN demonstrated inhibition of MAPK and phosphorylated MAPK on day 2. In post-SAH treatment study, antisense ODN reduced MAPK and phosphorylated MAPK in the basilar artery and attenuated cerebral vasospasm.
Conclusions:
MAPK activation, but not expression, might be implicated with sustained smooth muscle contraction during cerebral vasospasm after SAH. This study suggests that antisense MAPK ODN strategy is an effective treatment against cerebral vasospasm.
Insights
Mitogen-activated protein kinase (MAPK) activation, not expression, is linked to cerebral vasospasm after subarachnoid hemorrhage (SAH). Antisense MAPK oligodeoxynucleotide (ODN) effectively treats this condition.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Cerebral vasospasm following subarachnoid hemorrhage (SAH) is a critical complication.
- Mitogen-activated protein kinase (MAPK) pathways are implicated in vascular smooth muscle contraction.
Purpose of the Study:
- To investigate the role of MAPK expression and activation in the pathogenesis of cerebral vasospasm post-SAH.
- To evaluate the therapeutic potential of antisense MAPK oligodeoxynucleotide (ODN) for treating cerebral vasospasm.
Main Methods:
- Utilized a rat model of experimental subarachnoid hemorrhage (SAH).
- Administered antisense MAPK, sense MAPK, or scrambled oligodeoxynucleotides (ODNs) intracisternally.
- Assessed basilar artery vasospasm using histological parameters and quantified MAPK expression/activation via immunohistochemistry and Western blot.
Main Results:
- Antisense MAPK ODN significantly inhibited cerebral vasospasm compared to control ODNs on day 2 post-SAH.
- Immunohistochemistry and Western blot confirmed inhibition of MAPK and phosphorylated MAPK in the basilar artery.
- Post-SAH treatment with antisense ODN attenuated both MAPK activation and cerebral vasospasm.
Conclusions:
- MAPK activation, rather than expression, appears to be crucial for sustained smooth muscle contraction in cerebral vasospasm after SAH.
- Antisense MAPK ODN presents a promising therapeutic strategy for managing cerebral vasospasm.