title: Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia.
abstract: Delayed neuronal cell death occurring hours after reperfusion is a hallmark of ischemic stroke and a primary target for neuroprotective strategies. In the present study, we investigated whether apoptosis-inducing factor (AIF), a caspase-independent proapoptotic protein, is responsible for neuronal cell death after glutamate toxicity and oxygen-glucose deprivation (OGD) in vitro and after experimental stroke in vivo. AIF translocated to the nucleus in which it colocalized with DNA fragmentation and nuclear apoptotic morphology after exposure to glutamate or OGD in cultured neurons or after transient middle cerebral artery occlusion (MCAo) in mice. Small inhibitory RNA-mediated downregulation of AIF reduced glutamate- and OGD-induced neuronal apoptosis by 37 and 60%, respectively (p < 0.01). Moreover, Harlequin mutant mice, which express AIF at low levels (approximately 20% of wild-type mice), displayed smaller infarct volumes (-43%; p < 0.03) and showed dramatically reduced cell death in the ischemic penumbra after 45 min of MCAo compared with wild-type littermates. Inhibition of poly(ADP-ribose) polymerase and Bid reduced nuclear AIF translocation. These results provide the first evidence for a causal role of AIF in ischemic neuronal cell death. Therefore, caspase-independent cell death signaling may provide a promising novel target for therapeutic interventions in cerebrovascular diseases.
authors.affiliation: Department of Pharmacy, Walter Brendel Center for Experimental Medicine, University of Munich, D-81377 Munich, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.forename: Stefan
authors.initials: S
authors.lastname: Landshamer
authors.forename: Barbara
authors.initials: B
authors.lastname: Becattini
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellechia
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000502:physiology*; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D051381:Rats
chemical_list: D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; D011065:Poly(ADP-ribose) Polymerases; D005947:Glucose; D010100:Oxygen