on December 4, 2003
Published online before print December 4, 2003, doi: 10.1161/01.STR.0000106479.53235.3E
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Submitted on September 2, 2003
From the Department of Neurological Surgery (R.V., R.J.D., K.K.B.) and Cardiovascular Research Center (R.V.), University of Wisconsin at Madison. * To whom correspondence should be addressed. E-mail: Vemugant{at}neurosurg.wisc.edu.
Background and Purpose--The present study was performed to determine whether antisense inhibition of intercellular adhesion molecule-1 (ICAM-1) protein expression decreases focal ischemic brain damage. Methods--Male spontaneously hypertensive rats underwent 1-hour middle cerebral artery occlusion (MCAO) and 24-hour reperfusion. Rats were infused with ICAM-1 antisense or control oligodeoxynucleotides (ODNs) (48 nmol/d ICV) or vehicle, starting 24 hours before MCAO and continuing until the time of death. ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) mRNA levels were measured by real-time polymerase chain reaction. ICAM-1 protein knockdown was confirmed by Western blotting. Infarct volume was quantified by the use of cresyl violet-stained brain sections. Neurological deficits were evaluated. Mean arterial blood pressure was recorded by laser Doppler. Tissue penetration of antisense was confirmed by the use of fluorescent ODNs. Results--Transient MCAO upregulated ICAM-1, but not VCAM-1, mRNA expression in the ipsilateral cortex between 3 and 72 hours of reperfusion. ICAM-1 antisense infusion prevented ischemia-induced ICAM-1 protein expression and reduced total infarct volume (by 53%; P<0.05; 226±35 mm3 in control ODN group and 104±27 mm3 in antisense ODN group; n=8 each) and mean neurological deficit score (by 44%; P<0.05; 2.4 in control ODN group and 1.3 in antisense ODN group; n=8 each). Neither control nor antisense ODN had any effect on mean arterial blood pressure and the physiological parameters monitored during MCAO. Compared with noninfused control, intracerebroventricular infusion of artificial cerebrospinal fluid or antisense or sense ODN had no significant effect on the regional cerebral blood flow changes that accompanied ischemia and reperfusion. Conclusions--Increased ICAM-1 expression is implicated in the pathogenesis of focal ischemia since ICAM-1 protein knockdown decreased ischemic brain damage. The mechanism by which ICAM-1 inhibition offers neuroprotection is independent of blood pressure modulation.
Accepted on September 10, 2003
Inhibition of Intercellular Adhesion Molecule-1 Protein Expression by Antisense Oligonucleotides Is Neuroprotective After Transient Middle Cerebral Artery Occlusion in Rat
Raghu Vemuganti PhD*;
Key words: inflammation • intercellular adhesion molecule-1 • ischemia • neuroprotection • oligonucleotides, antisense • stroke
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