Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition.
One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.
Fukuda
H
H
Perinatal Center, Department of Physiology, Göteborg University, Box 432, SE 405 30 Göteborg, Sweden.
Fukuda
A
A
Zhu
C
C
Korhonen
L
L
Swanpalmer
J
J
Hertzman
S
S
Leist
M
M
Lannering
B
B
Lindholm
D
D
Björk-Eriksson
T
T
Marky
I
I
Blomgren
K
K
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D001921:Brain / Q000196:embryology*; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D049109:Cell Proliferation; D053938:DNA Fragmentation; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000473:pathology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D004676:Myelin Basic Protein; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D004921:Erythropoietin; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases