Nuclear factor-kappaB contributes to infarction after permanent focal ischemia

Stroke. 2004 Apr;35(4):987-91. doi: 10.1161/01.STR.0000120732.45951.26. Epub 2004 Feb 26.


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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Brain Ischemia / complications*
  • Cells, Cultured
  • Globins / genetics
  • Humans
  • Infarction, Middle Cerebral Artery / etiology*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • NF-kappa B p50 Subunit
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Inbred SHR
  • Stroke / metabolism
  • Thiocarbamates / pharmacology


  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Pyrrolidines
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Globins