Nuclear factor-κB contributes to infarction after permanent focal ischemia

Background and Purpose-Activation of transcription factor nuclear factor-kappaB (NF-kappaB) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-kappaB after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-kappaB-driven beta-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-kappaB and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate ( PDTC), an NF-kappaB inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-kappaB. Results-pMCAO increased NF-kappaB transcriptional activity to 260% (36.9+/-4.5 compared with 14.4+/-2.6; n=10; P<0.01) in the brain; this NF-kappa B activation was completely blocked by PDTC (17.2 +/- 2.6; n=9; P<0.05). In p50(-/-) mice, pMCAO resulted in 41% (18+/-3.2 mm(3); n=12) smaller infarcts compared with wild-type controls (32.9+/-3.8 mm(3); n=9; P<0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6 +/- 4.2 mm(3); n=8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-kappa B was activated in neurons in the penumbral areas. Conclusions-NF-kappa B is induced in neurons during human stroke, and activation of NF-kappa B in the brain may contribute to infarction in pMCAO.