Nuclear factor-kappaB contributes to infarction after permanent focal ischemia.
OBJECTIVE
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-kappaB 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 mm3; n=12) smaller infarcts compared with wild-type controls (32.9+/-3.8 mm3; n=9; P<0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6+/-4.2 mm3; 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-kappaB was activated in neurons in the penumbral areas.


CONCLUSIONS
NF-kappaB is induced in neurons during human stroke, and activation of NF-kappaB in the brain may contribute to infarction in pMCAO.
Nurmi
Antti
A
A.I. Virtanen Institute, Department of Neurobiology, University of Kuopio, Kuopio, Finland.
Lindsberg
Perttu J
PJ
Koistinaho
Milla
M
Zhang
Wen
W
Juettler
Eric
E
Karjalainen-Lindsberg
Marja-Liisa
ML
Weih
Falk
F
Frank
Norbert
N
Schwaninger
Markus
M
Koistinaho
Jari
J
D000328:Adult; D000368:Aged; D000818:Animals; D002545:Brain Ischemia / Q000150:complications*; D002478:Cells, Cultured; D005914:Globins / Q000235:genetics; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D005914:Globins