Recombinant adenoviral expression of dominant negative IkappaBalpha protects brain from cerebral ischemic injury.
Transcription factor NF-kappaB is associated with inflammatory response and cell survival. Under inactive condition, NF-kappaB is sequestered in the cytoplasm by an anchor protein, inhibitor of NF-kappaB (IkappaB). NF-kappaB was shown to be activated during ischemic brain injury. In the present study we have investigated the role of NF-kappaB in ischemic brain injury using a recombinant adenovirus expressing a dominant negative form of IkappaB (Adv/IkappaBdn) to specifically inhibit NF-kappaB activation. Our data demonstrated that cortical injection of Adv/IkappaBdn significantly reduced ischemic brain injury following permanent occlusion of the middle cerebral artery (MCAO) in rats, showing 55% reduction (p<0.01, n=8) in total ischemic lesion or 80% reduction (p<0.001) in the cortical area with Adv/IkappaBdn expression. Similarly, Adv/IkappaBdn expression significantly decreased neurological deficits (37% reduction over controls, p<0.01, n=8). These data provide further evidence for the role of NF-kappaB/IkappaB in ischemic brain injury and suggest that inhibition of NF-kappaB is neuroprotective in focal stroke.
Xu
Lin
L
Department of Cardiovascular Sciences, Bristol-Myers Squibb Company, Experimental Station, E400/3418, Wilmington, DE 19880-0400, USA.
Zhan
Yutian
Y
Wang
Yibin
Y
Feuerstein
Giora Z
GZ
Wang
Xinkang
X
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D005799:Genes, Dominant; D020672:I-kappa B Proteins / Q000235:genetics* / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha