NF-kappaB protects neurons from ischemic injury after middle cerebral artery occlusion in mice.
Knowledge about the molecular mechanisms of neuronal survival following ischemia is crucial to the development of therapeutic interventions for victims of stroke. Previous research in our laboratory has implicated nuclear factor-kappaB (NF-kappaB) as contributing to neuronal survival in response to toxic or ischemic brain insult, with in vivo models having focused on the rat. To take advantage of genetic alterations available in the mouse, we utilized a murine transient endovascular middle cerebral artery occlusion (MCAO) model to examine the influence of NF-kappaB on neuronal survival. When brains were immunostained for the nuclear localization sequence (NLS) of the p50 subunit of NF-kappaB, a unilateral increase in immunoreactivity was seen, especially in pyramidal cell layers of the ipsilateral (stroked) hippocampus. When transgenic mice lacking p50 were compared with non-transgenic counterparts using Fluoro-Jade, a marker for neurodegeneration, both the hippocampus and striatum showed enhanced neurodegeneration at various survival times after 1 h of MCAO. In the hippocampus specifically, there was an eightfold increase in Fluoro-jade staining in the p50 knockout group vs. the non-transgenic group. Sections double stained for Fluoro-Jade and NF-kappaB activity (using a mouse engineered with a NF-kappaB responsive promoter driving a LacZ gene to produce beta galactosidase) demonstrated neuronal degeneration only in regions sparsely showing NF-kappaB activity, and those demonstrating NF-kappaB activity failed to degenerate. These data provide evidence that NF-kappaB participates in survival signaling following temporary focal ischemia, and thus may represent an attractive target for pharmacologic activation in the treatment of stroke.
Duckworth
Edward A M
EA
Department of Neurological Surgery, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Butler
Tanya
T
Collier
Lisa
L
Collier
Shane
S
Pennypacker
Keith R
KR
D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D003952:Diagnostic Imaging / Q000379:methods; D005452:Fluoresceins; D007839:Functional Laterality; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D009930:Organic Chemicals / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D005452:Fluoresceins; D016328:NF-kappa B; D009930:Organic Chemicals; C435731:fluoro jade; D001616:beta-Galactosidase