Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain.
Apoptosis-inducing factor (AIF) triggers apoptosis in a caspase-independent manner. Here we report for the first time involvement of AIF in neuronal death induced by cerebral ischemia. Unilateral cerebral hypoxia-ischemia (HI) was induced in 7-day-old rats by ligation of the left carotid artery and hypoxia (7.7% O2) for 55 min. AIF release from mitochondria and AIF translocation to nuclei was detected immediately after HI, and only in damaged areas, as judged by the concurrent loss of MAP-2. AIF release was detected earlier than that of cytochrome c. Cells with AIF-positive nuclei displayed nuclear condensation and signs of DNA damage. The number of AIF-positive nuclei showed a positive correlation with the infarct volume 72 h post-HI, and this was not changed by treating the animals with boc-Asp-fmk (BAF), a multicaspase inhibitor. BAF treatment reduced the activity of caspase-3, -2 and -9 (78, 73 and 33%, respectively), and prevented caspase-dependent fodrin cleavage in vivo, but did not affect AIF release from mitochondria or the frequency of positive nuclear AIF or DNA damage 72 h post-HI, indicating that these processes occurred in a caspase-independent fashion. In summary, AIF-mediated cell death may be an important mechanism of HI-induced neuronal loss in the immature brain.
Zhu
Changlian
C
Perinatal Center, Department of Physiology, Göteborg University, Göteborg, Sweden.
Qiu
Lin
L
Wang
Xiaoyang
X
Hallin
Ulrika
U
Candé
Céline
C
Kroemer
Guido
G
Hagberg
Henrik
H
Blomgren
Klas
K
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005420:Flavoproteins / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013049:Spectrin
D000590:Amino Acid Chloromethyl Ketones; D051033:Apoptosis Inducing Factor; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D005420:Flavoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D013049:Spectrin; C494831:Aifm1 protein, rat; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone