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The Journal of Neuroscience, October 15, 1999, 19(20):8856-8865
Lack of the p50 Subunit of Nuclear Factor- B Increases the
Vulnerability of Hippocampal Neurons to Excitotoxic Injury
ZaiFang
Yu1,
Daohong
Zhou2,
Annadora J.
Bruce-Keller1, 3,
Mark S.
Kindy1, 4, and
Mark P.
Mattson1, 5
1 Sanders-Brown Research Center on Aging,
2 Division of Allergy, Immunology, and Rheumatology and
Department of Internal Medicine, and Departments of
3 Physiology, 4 Biochemistry, and
5 Anatomy and Neurobiology, University of Kentucky,
Lexington, Kentucky 40536
Nuclear factor- B (NF-B) is activated in brain cells after
various insults, including cerebral ischemia and epileptic seizures. Although cell culture studies have suggested that the activation of
NF-B can prevent neuronal apoptosis, the role of this transcription factor in neuronal injury in vivo is unclear, and the
specific B subunits involved are unknown. We now report that mice
lacking the p50 subunit of NF-B exhibit increased damage to
hippocampal pyramidal neurons after administration of the excitotoxin
kainate. Gel-shift analyses showed that p50 is required for the
majority of B DNA-binding activity in hippocampus. Intraventricular
administration of B decoy DNA before kainate administration in
wild-type mice resulted in an enhancement of damage to hippocampal
pyramidal neurons, indicating that reduced NF-B activity was
sufficient to account for the enhanced excitotoxic neuronal injury in
p50 / mice. Cultured hippocampal neurons from
p50/ mice exhibited enhanced elevations of
intracellular calcium levels and increased levels of oxidative stress
after exposure to glutamate and were more vulnerable to excitotoxicity
than were neurons from p50+/+ and
p50+/ mice. Collectively, our data demonstrate an
important role for the p50 subunit of NF-B in protecting neurons
against excitotoxic cell death.
Key words:
calcium; epileptic seizures; hippocampus; kainic acid; stroke; superoxide dismutase; transcription; tumor necrosis factor
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208856-10$05.00/0
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