Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain

Changlian Zhu, Lin Qiu, Xiaoyang Wang, Ulrika Hallin, Céline Candé, Guido Kroemer, Henrik Hagberg, Klas Blomgren

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    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)306-317
    Nombre de pages12
    journalJournal of Neurochemistry
    Volume86
    Numéro de publication2
    Les DOIs
    étatPublié - 1 juil. 2003

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