Significant Role of Apoptosis-Inducing Factor (AIF) for Brain Damage Following Focal Cerebral Ischemia



Every year, stroke is responsible for the death of 5.5 million people and thus accounts for 10% of all deaths in industrialized countries worldwide (Mackay and Mensah 2004). Despite such a high incidence and mortality, therapeutic options for stroke patients are still very limited (Lo et al. 2003). Currently, the only clinical treatment option for stroke is reperfusion therapy by local or systemic administration of recombinant tissue plasminogen activator (rtPA). A major drawback of rtPA, however, is that it may be fatal if given in hemorrhagic stroke, which has clinical symptoms very similar to ischemic stroke. Accordingly, rtPA therapy can only be initiated after cerebral hemorrhage has been ruled out by brain CT or NMR imaging. By the time diagnostic procedures have been completed, the therapeutic window for rtPA, i.e. 3 h after the onset of ischemia, has commonly closed. As a result less than 5% of all stroke patients are eligible for rtPA lysis according to current protocols (Adams et al. 2007). The remaining 95% may only hope for spontaneous reperfusion, which in most cases, however, occurs too late to prevent penumbral cell death and the subsequent loss of neurological function (Molina et al. 2001). Hence, a treatment strategy is required, which prolongs neuronal survival in the ischemic penumbra, i.e. under compromised cerebral blood flow conditions, until reperfusion occurs.


Middle Cerebral Artery Occlusion Neuronal Cell Death Focal Cerebral Ischemia Ischemic Penumbra Recombinant Tissue Plasminogen Activator 


  1. Adams HP Jr, Del ZG, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF (2007) Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 115:e478–e534PubMedCrossRefGoogle Scholar
  2. Astrup J, Siesjo BK, Symon L (1981) Thresholds in cerebral ischemia - the ischemic penumbra. Stroke 12:723–725PubMedGoogle Scholar
  3. Becattini B, Culmsee C, Leone M, Zhai D, Zhang X, Crowell KJ, Rega MF, Landshamer S, Reed JC, Plesnila N, Pellecchia M (2006) Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid. Proc Natl Acad Sci USA 103:12602–12606PubMedCrossRefGoogle Scholar
  4. Cao G, Pei W, Lan J, Stetler RA, Luo Y, Nagayama T, Graham SH, Yin XM, Simon RP, Chen J (2001) Caspase-activated DNase/DNA fragmentation factor 40 mediates apoptotic DNA fragmentation in transient cerebral ischemia and in neuronal cultures. J Neurosci 21:4678–4690PubMedGoogle Scholar
  5. Cao G, Pei W, Ge H, Liang Q, Luo Y, Sharp FR, Lu A, Ran R, Graham SH, Chen J (2002) In Vivo Delivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis. J Neurosci 22:5423–5431PubMedGoogle Scholar
  6. Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, Graham SH, Chen J (2003) Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab 23:1137–1150PubMedCrossRefGoogle Scholar
  7. Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben Ari Y (1996) Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194PubMedCrossRefGoogle Scholar
  8. Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158:507–517PubMedCrossRefGoogle Scholar
  9. Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272PubMedCrossRefGoogle Scholar
  10. Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476:118–123PubMedCrossRefGoogle Scholar
  11. Du C, Hu R, Csernansky CA, Hsu CY, Choi DW (1996) Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 16:195–201PubMedCrossRefGoogle Scholar
  12. Endres M, Namura S, Shimizu-Sasamata M, Waeber C, Zhang L, Gomez-Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247PubMedCrossRefGoogle Scholar
  13. Fujimura M, Morita-Fujimura Y, Noshita N, Sugawara T, Kawase M, Chan PH (2000) The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice. J Neurosci 20:2817–2824PubMedGoogle Scholar
  14. Kilic E, Dietz GP, Hermann DM, Bahr M (2002) Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in mice. Ann Neurol 52:617–622PubMedCrossRefGoogle Scholar
  15. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL (2002) The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 419:367–374PubMedCrossRefGoogle Scholar
  16. Landshamer S, Hoehn M, Barth N, Duvezin-Caubet S, Schwake G, Tobaben S, Kazhdan I, Becattini B, Zahler S, Vollmar A, Pellecchia M, Reichert A, Plesnila N, Wagner E, Culmsee C (2008) Bid-induced release of AIF from mitochondria causes immediate neuronal cell death. Cell Death Differ 15(10):1553–1563PubMedCrossRefGoogle Scholar
  17. Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, Hyman BT, Yuan J, Kuida K, Flavell RA, Moskowitz MA (2002) Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 99:15188–15193PubMedCrossRefGoogle Scholar
  18. Lee BI, Chan PH, Kim GW (2005) Metalloporphyrin-based superoxide dismutase mimic attenuates the nuclear translocation of apoptosis-inducing factor and the subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. Stroke 36:2712–2717PubMedCrossRefGoogle Scholar
  19. Lee JH, Park SY, Shin HK, Kim CD, Lee WS, Hong KW (2007) Poly(ADP-ribose) polymerase inhibition by cilostazol is implicated in the neuroprotective effect against focal cerebral ischemic infarct in rat. Brain Res 1152:182–190PubMedCrossRefGoogle Scholar
  20. Li X, Nemoto M, Xu Z, Yu SW, Shimoji M, Andrabi SA, Haince JF, Poirier GG, Dawson TM, Dawson VL, Koehler RC (2007) Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus. Neuroscience 144:56–65PubMedCrossRefGoogle Scholar
  21. Linnik MD, Miller JA, Sprinkle-Cavallo J, Mason PJ, Thompson FY, Montgomery LR, Schroeder KK (1995) Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. Brain Res Mol Brain Res 32:116–124PubMedCrossRefGoogle Scholar
  22. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415PubMedCrossRefGoogle Scholar
  23. Mackay J, Mensah G (2004) Atlas of heart disease and stroke. World Health Organization.Google Scholar
  24. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030PubMedCrossRefGoogle Scholar
  25. Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, Schenkel J, Herdegen T, Debatin KM (1999) CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci 19:3809–3817PubMedGoogle Scholar
  26. Molina CA, Montaner J, Abilleira S, Ibarra B, Romero F, Arenillas JF, Alvarez-Sabin J (2001) Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke 32:1079–1084PubMedCrossRefGoogle Scholar
  27. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668PubMedGoogle Scholar
  28. Plesnila N (2004) Role of mitochondrial proteins for neuronal cell death after focal cerebral ischemia. Acta Neurochir Suppl 89:15–19PubMedGoogle Scholar
  29. Plesnila N, Zinkel S, Le DA, Amin-Hanjani S, Wu Y, Qiu J, Chiarugi A, Thomas SS, Kohane DS, Korsmeyer SJ, Moskowitz MA (2001) BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci USA 98:15318–15323PubMedCrossRefGoogle Scholar
  30. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466PubMedCrossRefGoogle Scholar
  31. Rideout HJ, Stefanis L (2001) Caspase inhibition: a potential therapeutic strategy in neurological diseases. Histol Histopathol 16:895–908PubMedGoogle Scholar
  32. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedCrossRefGoogle Scholar
  33. Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ (1999) Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 19:5932–5941PubMedGoogle Scholar
  34. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071PubMedGoogle Scholar
  35. Wei G, Wang D, Lu H, Parmentier S, Wang Q, Panter SS, Frey WH, Ying W (2007) Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury. Front Biosci 12:4986–4996PubMedCrossRefGoogle Scholar
  36. Wiessner C, Allegrini PR, Rupalla K, Sauer D, Oltersdorf T, McGregor AL, Bischoff S, Bottiger BW, van der PH (1999) Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci Lett 268:119–122PubMedCrossRefGoogle Scholar
  37. Yin XM, Luo Y, Cao G, Bai L, Pei W, Kuharsky DK, Chen J (2002) Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia. J Biol Chem 277:42074–42081PubMedCrossRefGoogle Scholar
  38. Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ (2000) Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290:1761–1765PubMedCrossRefGoogle Scholar
  39. Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 86:306–317PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Neurodegeneration and Department of PhysiologyRoyal College of Surgeons in Ireland (RCSI)DublinIreland
  2. 2.Clinical Pharmacy–Pharmacology and ToxicologyPhilipps-University of MarburgMarburgGermany

Personalised recommendations