TY - JOUR
T1 - Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury
AU - Graham, Ernest M.
AU - Sheldon, R. Ann
AU - Flock, Debra L.
AU - Ferriero, Donna M.
AU - Martin, Lee J.
AU - O'Riordan, Declan P.
AU - Northington, Frances J.
N1 - Funding Information:
These studies were supported by NS 45059, HD 39672 (FJN), United Cerebral Palsy (FJN), U.S. Army Department of Defense DAMD17-99-1-9553, NIH AG16282 (LJM), and NS 35902 (DMF).
PY - 2004/10
Y1 - 2004/10
N2 - Neonatal hypoxia-ischemia (HI) upregulates Fas death receptor expression in the brain, and alterations in expression and activity of Fas signaling intermediates occur in neonatal brain injury. B6.MRL-Tnfrsf6lpr mice lacking functional Fas death receptors are protected from HI brain damage in cortex, striatum, and thalamus compared to wild-type mice. Expression of Fas death receptor and active caspases increase in the cortex after HI. In wild-type mice, the hippocampus is most severely injured, and the hippocampus is the only region not protected in the B6.MRL-Tnfrsf6lpr mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1β-converting enzyme]-inhibitory protein (FLIP), (2) increased degradation of spectrin to its 145 or 150 kDa breakdown product, and (3) a higher percentage of non-apoptotic cell death following neonatal HI. We conclude that Fas signaling via both extrinsic and intrinsic caspase cascades causes brain injury following neonatal HI in a region-dependent manner. Basal levels of endogenous decoy proteins may modulate the response to Fas death receptor signaling and provide a novel approach to understanding mechanisms of neonatal brain injury.
AB - Neonatal hypoxia-ischemia (HI) upregulates Fas death receptor expression in the brain, and alterations in expression and activity of Fas signaling intermediates occur in neonatal brain injury. B6.MRL-Tnfrsf6lpr mice lacking functional Fas death receptors are protected from HI brain damage in cortex, striatum, and thalamus compared to wild-type mice. Expression of Fas death receptor and active caspases increase in the cortex after HI. In wild-type mice, the hippocampus is most severely injured, and the hippocampus is the only region not protected in the B6.MRL-Tnfrsf6lpr mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1β-converting enzyme]-inhibitory protein (FLIP), (2) increased degradation of spectrin to its 145 or 150 kDa breakdown product, and (3) a higher percentage of non-apoptotic cell death following neonatal HI. We conclude that Fas signaling via both extrinsic and intrinsic caspase cascades causes brain injury following neonatal HI in a region-dependent manner. Basal levels of endogenous decoy proteins may modulate the response to Fas death receptor signaling and provide a novel approach to understanding mechanisms of neonatal brain injury.
KW - Apoptosis
KW - Cell death phenotype
KW - Hypoxia-ischemia
KW - Perinatal brain injury
KW - Regional brain vulnerability
KW - TNF receptors
KW - [Fas-associated death-domain-like IL-1β-converting enzyme]-inhibitory protein (FLIP)
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U2 - 10.1016/j.nbd.2004.05.007
DO - 10.1016/j.nbd.2004.05.007
M3 - Article
C2 - 15350969
AN - SCOPUS:4444377604
VL - 17
SP - 89
EP - 98
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -