Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke.
Nuclear factor-kappaB (NFkappaB) is a transcription factor that is activated after cerebral ischemia. NFkappaB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. The authors previously showed that mild hypothermia is protective even when cooling begins 2 h after stroke onset. In the present study, they examined the influence of hypothermia on NFkappaB activation. Rats underwent 2 h of transient middle cerebral artery occlusion. Brains were cooled to 33 degrees C immediately after or 2 h after occlusion, and maintained for 2 h. After normothermic ischemia (brain temperature at 38 degrees C), NFkappaB cytoplasmic expression, nuclear translocation, and binding activity were observed as early as 2 h in the ischemic hemisphere and persisted at 24 h. Hypothermia decreased NFkappaB translocation and binding activity but did not alter overall expression. Hypothermia also affected the levels of NFkappaB regulatory proteins by suppressing phosphorylation of NFkappaB's inhibitory protein (IkappaB-alpha) and IkappaB kinase (IKK-gamma) and decreasing IKK activity, but did not alter overall IKK levels. Hypothermia suppressed the expression of two NFkappaB target genes: inducible nitric oxide synthase and TNF-alpha. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFkappaB inhibition due to decreased activity of IKK.
Han
Hyung Soo
HS
Department of Neurosurgery, Stanford University Medical Center, Stanford, California 94305, U.S.A.
Karabiyikoglu
Murat
M
Kelly
Stephen
S
Sobel
Raymond A
RA
Yenari
Midori A
MA
D000818:Animals; D015153:Blotting, Western; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015870:Gene Expression; D007036:Hypothermia, Induced; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase