Inhibitory effect with antisense mitogen-activated protein kinase oligodeoxynucleotide against cerebral vasospasm in rats.
OBJECTIVE
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.
Satoh
Motoyoshi
M
Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Miss 39216, USA.
Parent
Andrew D
AD
Zhang
John H
JH
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000150:complications; D016896:Treatment Outcome; D014654:Vascular Patency / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D016376:Oligonucleotides, Antisense; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases