Advances in Neuronal Cell Death 2007
2008; Lippincott Williams & Wilkins; Volume: 39; Issue: 2 Linguagem: Inglês
10.1161/strokeaha.107.511857
ISSN1524-4628
AutoresMaged M. Harraz, Ted M. Dawson, Valina L. Dawson,
Tópico(s)CRISPR and Genetic Engineering
ResumoHomeStrokeVol. 39, No. 2Advances in Neuronal Cell Death 2007 Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAdvances in Neuronal Cell Death 2007 Maged M. Harraz, MD, PhD, Ted M. Dawson, MD, PhD and Valina L. Dawson, PhD Maged M. HarrazMaged M. Harraz From the Institute for Cell Engineering (M.M.H., T.M.D., V.L.D.), Departments of Neurology (M.M.H., T.M.D., V.L.D.), Neuroscience (T.M.D., V.L.D.), and Physiology (V.L.D.), The Johns Hopkins University School of Medicine, Baltimore, Md, USA. , Ted M. DawsonTed M. Dawson From the Institute for Cell Engineering (M.M.H., T.M.D., V.L.D.), Departments of Neurology (M.M.H., T.M.D., V.L.D.), Neuroscience (T.M.D., V.L.D.), and Physiology (V.L.D.), The Johns Hopkins University School of Medicine, Baltimore, Md, USA. and Valina L. DawsonValina L. Dawson From the Institute for Cell Engineering (M.M.H., T.M.D., V.L.D.), Departments of Neurology (M.M.H., T.M.D., V.L.D.), Neuroscience (T.M.D., V.L.D.), and Physiology (V.L.D.), The Johns Hopkins University School of Medicine, Baltimore, Md, USA. Originally published10 Jan 2008https://doi.org/10.1161/STROKEAHA.107.511857Stroke. 2008;39:286–288Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 10, 2008: Previous Version 1 In a stroke lesion, there is a core of necrotic cell death surrounded by a zone of tissue at risk, termed the penumbra. In the penumbra, there is usually less severe tissue damage. Programmed cell death (PCD) pathways have been documented to be present in the penumbra. While many studies have used the term apoptosis as equivalent to PCD, the absence of complete biochemical and morphological characteristics of apoptosis, coupled with the ineffectiveness of caspase inhibitors, indicates that there are other important cell death pathways activated during stroke. A few caspase-independent cell death pathways have been identified and there are likely more to be described.ParthanatosStroke injury leads to the activation of a cell death program, dependent on poly(ADP-ribose) polymerase-1 (PARP1) activation1 and culminating in apoptosis inducing factor (AIF) mediated cell death.2 Poly(ADP-ribose) (PAR) polymer is the death signal in this pathway and Thanatos is the Greek personification of death and mortality, hence, the name parthanatos. In this form of cell death that occurs in many different organ systems during ischemia-reperfusion injury, PAR polymer translocates from the nucleus to the cytoplasm and mitochondria. This leads to release of AIF from the mitochondria, an effect that is inhibited by poly(ADP-ribose) glycohydrolase (PARG), an enzyme that degrades PAR polymer.3 After cerebral focal ischemia reperfusion injury, mice with reduced PARG levels had higher infarct volumes than controls. On the other hand, mice overexpressing PARG had significantly lower infarct volumes. Combined, the current data indicate that PAR is a powerful death signal. What is not yet understood are the mechanisms of PAR translocation out of the nucleus and PAR-mediated AIF release from the mitochondria. Parthanatos is caspase-independent and is biochemically and morphologically distinct from apoptosis.4 Regulation of PAR signaling may be a useful therapeutic intervention to reduce stroke-mediated damage.Apoptosis-Inducing FactorAdditional investigations this year have explored the role of AIF during stroke. In an elegant piece of work, investigators studied the actions of the calcium-dependent protease, calpain I, on the release of AIF. The role of calpains in mediating neuronal injury has been controversial, which may be, in part, due to nonspecific reagents and the variability of the experimental models. In this study, calpain I cleaves an N-terminal fragment from AIF, leading to its liberation from HSP10 in the mitochondria, which may then render AIF available for release from the mitochondria. Calpastatin, an inhibitor of calpain activity, was shown to provide neuroprotection, as was knockdown of AIF during cerebral transient ischemia, further supporting a role for calpain in the release of AIF and subsequent neuronal injury after stroke.5 The question that remains is whether calpain-mediated release of AIF is a parallel pathway independent of PAR or whether PAR participates with calpain to release AIF. There is suggestive data, in mouse embryonic fibroblasts, treated with DNA damaging alkylating agents, that PARP1 and AIF-dependent cell death may involve p53, Bax and calpains, but not Bak, caspases or PARP2.6 The study used a series of genetically modified cells and time course analysis to define a molecular signaling sequence of PARP1, calpain activation, Bax and AIF translocation in cell death due to DNA damage. These data are provocative, but the study was conducted in engineered mitotic cells. Further work in experimental neuronal systems is required.Another player in the field of AIF release in stroke is cyclophilin A, a protein that is highly expressed in the cytoplasm and nucleus of neurons. Cyclophilin A has been implicated in various models of cell death and, in the Rice-Vannucci model of experimental ischemic stroke performed in 9 day old mice, cyclophilin A deficiency is neuroprotective and AIF does not translocate to the nucleus. These data suggest that cyclophilin A may physically interact with AIF after ischemic injury, but not under normal physiological conditions.7Other Caspase-Independent Cell DeathBNIP3 belongs to a growing family of mitochondrial death signals. It is not detectable in neurons under physiological conditions, but BNIP3 protein expression is induced by hypoxia. After 90 minutes of middle cerebral artery occlusion in rats, BNIP3 is upregulated 48 hours after focal brain ischemia reperfusion in ischemic tissue, but not in nonischemic tissue.8 Knockdown of BNIP3 expression in primary cortical cultures delays neuronal cell death after hypoxia; however, a role for BNIP3 in oxygen-glucose deprivation, more commonly used in vitro as a culture model of middle cerebral artery occlusion, was not explored. It is possible that BNIP3 might mediate EndoG translocation from the mitochondria. However, there is concern regarding the specificity of the EndoG antibodies, which are not well characterized. It is difficult to understand how a matrix protein, such as EndoG, could have a specific release mechanism involving BNIP3 or whether translocation occurs after rupture of mitochondrial membranes.8EnergyPARP1-dependent cell death is believed to result, at least partially, from NAD+ depletion. Both genotoxic stress and nutrient deprivation activate PARP1 and result in NAD+ depletion. However, mitochondrial NAD+ levels are not reduced following those stressors.9 Nampt, an enzyme involved in NAD+ biogenesis, protects cells from death by genotoxic stress, an effect that is mediated by regulating mitochondrial NAD+ levels. In addition, Nampt inhibited AIF translocation to the nucleus following genotoxic stress.9 These studies emphasize the importance of investigating the subcellular levels of NAD+ versus total levels in experimental models of stroke. It will be interesting to determine if Nampt plays a role in parthanatos after ischemia reperfusion injury in the brain and whether it has a neuroprotective action in stroke.Endoplasmic Reticulum Stress and AutophagyEndoplasmic reticulum (ER) stress induced neuronal cell death plays an important role in stroke pathophysiology.10 BBF2H7 is a novel ER stress transducer with interesting potential as a candidate for neuroprotection. BBF2H7 appears to be expressed in the peri-infarction zone after permanent focal brain ischemia, but not in the nonischemic neurons.11 In neuroblastoma cells, overexpression of BBF2H7 suppresses and conversely knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, these data suggest a role for BBF2H7 and ER stress in ischemic injury; however, changes in protein expression do not necessarily define a functional role in ischemic injury and may instead be bystander events triggered by severe stress. Additionally, the cell death assays were performed in tumor cell lines and have not yet been replicated in neurons or the brain. Thus, while intriguing, any interpretation must be cautiously made.The role of autophagy in neuronal cell death is an emerging area of cell death research. Autophagy can be triggered by ER stress and oxidative stress, poising it to be a key player in ischemic cell death. Autophagy is a lysosomal pathway important for the turnover of organelles and proteins that can be induced in neurons.12 Autophagy has only recently been recognized as an important process that may be a key regulator of neurodegenerative processes. Recent studies implicate a role for autophagy in the prenumbra after experimental stroke. Beclin 1 and microtubule-associated protein 1 light chain 3, which are known to promote autophagy are induced in the penumbra of rats after 90 minutes middle cerebral artery occlusion.13 Both genetic disruption and chemical inhibition of autophagy inhibit necrosis induced by 40 minutes of hypoxia in Celegans.14 Taken together with the observation of autophagic morphology following the modified Levine/Vannucci procedure in adult mice,15 these early studies suggest that autophagic cell death may be a critically important form of cell death in the nervous system that has, until recently, been overlooked.Summary"Death Hath so Many Doors to Let Out Life." —John Fletcher & Francis BeaumontWhile life and death are binary events, there are many different pathways for cells to die. We are just coming to the realization that there is more to cell death than apoptosis and necrosis, which implies that our understanding of cell death in the brain is severely restricted. Until we understand the primary pathways that result in cell death after ischemia, we will not be able to define new and effective therapies. Several advances this year are predictive of future studies. When AIF was first identified, it was thought that AIF mediated a very specific and restricted form of caspase-independent cell death. We are now finding that AIF belongs to the growing family of mitochondrial death effectors and that many different signaling events can lead to AIF release. AIF can be released as a commitment point to cell death, but it can also be released later in the cell death cycle. Nuclear AIF is a promiscuous marker for cell death; therefore, it is important to determine whether AIF translocation is a primary causal event in the cell death process by blocking AIF translocation. Additional work is necessary to fully understand the role of AIF in neuronal cell death. There is a growing number of caspase-independent cell death effectors being identified in the brain, but a lot of work is required in order to understand which are primary causal events, toward which therapeutics might be targeted, and which are secondary and perhaps less important events. Along these lines, PAR signaling appears to be an important primary event that would be amenable for therapeutic development. Lastly, autophagy is likely to be a very fruitful frontier for understanding the response of the brain to stress and injury. Cell death due to autophagy may turn out to be one of the more important cell death signaling events in the brain and is a relatively untapped area of research.We thank K. Quinn Tyler for editorial assistance.Sources of FundingThis work was supported by USPHS NS039148, DA000266. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.DisclosuresNone.FootnotesCorrespondence to Valina L. Dawson, PhD, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD 21205, USA. E-mail [email protected] References 1 Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL. Poly(adp-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997; 3: 1089–1095.CrossrefMedlineGoogle Scholar2 Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of poly(adp-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002; 297: 259–263.CrossrefMedlineGoogle Scholar3 Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL. Apoptosis-inducing factor mediates poly(adp-ribose) (par) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006; 103: 18314–18319.CrossrefMedlineGoogle Scholar4 Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM. Poly(adp-ribose) (par) polymer is a death signal. Proc Natl Acad Sci U S A. 2006; 103: 18308–18313.CrossrefMedlineGoogle Scholar5 Cao G, Xing J, Xiao X, Liou AK, Gao Y, Yin XM, Clark RS, Graham SH, Chen J. Critical role of calpain i in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci. 2007; 27: 9278–9293.CrossrefMedlineGoogle Scholar6 Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA. Sequential activation of poly(adp-ribose) polymerase 1, calpains, and bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol. 2007; 27: 4844–4862.CrossrefMedlineGoogle Scholar7 Zhu C, Wang X, Deinum J, Huang Z, Gao J, Modjtahedi N, Neagu MR, Nilsson M, Eriksson PS, Hagberg H, Luban J, Kroemer G, Blomgren K. Cyclophilin a participates in the nuclear translocation of apoptosis-inducing factor in neurons after cerebral hypoxia-ischemia. J Exp Med. 2007; 204: 1741–1748.CrossrefMedlineGoogle Scholar8 Zhang Z, Yang X, Zhang S, Ma X, Kong J. Bnip3 upregulation and endog translocation in delayed neuronal death in stroke and in hypoxia. Stroke. 2007; 38: 1606–1613.LinkGoogle Scholar9 Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA. Nutrient-sensitive mitochondrial nad+ levels dictate cell survival. Cell. 2007; 130: 1095–1107.CrossrefMedlineGoogle Scholar10 Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y, Mori M. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving chop. Cell Death Differ. 2004; 11: 403–415.CrossrefMedlineGoogle Scholar11 Kondo S, Saito A, Hino S, Murakami T, Ogata M, Kanemoto S, Nara S, Yamashita A, Yoshinaga K, Hara H, Imaizumi K. Bbf2h7, a novel transmembrane bzip transcription factor, is a new type of endoplasmic reticulum stress transducer. Mol Cell Biol. 2007; 27: 1716–1729.CrossrefMedlineGoogle Scholar12 Boland B, Nixon RA. Neuronal macroautophagy: from development to degeneration. Mol Aspects Med. 2006; 27: 503–519.CrossrefMedlineGoogle Scholar13 Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of beclin 1 and autophagy-like cell death. Neurobiol Dis. 2008; 29: 132–141.CrossrefMedlineGoogle Scholar14 Samara C, Syntichaki P, Tavernarakis N Autophagy is required for necrotic cell death in caenorhabditis elegans. Cell Death Differ. 2008; 15: 105–112.CrossrefMedlineGoogle Scholar15 Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR, Kuan CY. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol. 2006; 169: 566–583.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Heib M, Weiß J, Saggau C, Hoyer J, Fuchslocher Chico J, Voigt S and Adam D (2022) Ars moriendi: Proteases as sculptors of cellular suicide, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 10.1016/j.bbamcr.2021.119191, 1869:4, (119191), Online publication date: 1-Apr-2022. Nan L, Xie Q, Chen Z, Zhang Y, Chen Y, Li H, Lai W, Chen Y and Huang M (2019) Involvement of PARP-1/AIF Signaling Pathway in Protective Effects of Gualou Guizhi Decoction Against Ischemia–Reperfusion Injury-Induced Apoptosis, Neurochemical Research, 10.1007/s11064-019-02912-3, 45:2, (278-294), Online publication date: 1-Feb-2020. Su C and Xu Y (2020) The evolving roles of radiolabeled quinones as small molecular probes in necrotic imaging, The British Journal of Radiology, 10.1259/bjr.20200034, 93:1111, (20200034), Online publication date: 1-Jul-2020. Kim J, Kim J, Roh J, Park C, Seoh J and Hwang E (2018) Reactive oxygen species-induced parthanatos of immunocytes by human cytomegalovirus-associated substance, Microbiology and Immunology, 10.1111/1348-0421.12575, 62:4, (229-242), Online publication date: 1-Apr-2018. Fatokun A (2018) Parthanatos: Poly ADP Ribose Polymerase (PARP)-Mediated Cell Death Apoptosis and Beyond, 10.1002/9781119432463.ch25, (535-558) Santulli C, Brizi C, Micucci M, Del Genio A, De Cristofaro A, Bracco F, Pepe G, di Perna I, Budriesi R, Chiarini A and Frosini M (2016) Castanea sativa Mill. Bark Extract Protects U-373 MG Cells and Rat Brain Slices Against Ischemia and Reperfusion Injury , Journal of Cellular Biochemistry, 10.1002/jcb.25760, 118:4, (839-850), Online publication date: 1-Apr-2017. Luo T, Yuan Y, Yu Q, Liu G, Long M, Zhang K, Bian J, Gu J, Zou H, Wang Y, Zhu J, Liu X and Liu Z (2017) PARP-1 overexpression contributes to Cadmium-induced death in rat proximal tubular cells via parthanatos and the MAPK signalling pathway, Scientific Reports, 10.1038/s41598-017-04555-2, 7:1, Online publication date: 1-Dec-2017. Nakka V, Prakash-babu P and Vemuganti R (2014) Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries, Molecular Neurobiology, 10.1007/s12035-014-9029-6, 53:1, (532-544), Online publication date: 1-Jan-2016. Takasawa S, Itaya-Hironaka A, Yamauchi A, Ota H, Takeda M, Sakuramoto-Tsuchida S, Fujimura T and Tsujinaka H (2016) Regulators of Beta-Cell Death and Regeneration Pancreatic Islet Biology, 10.1007/978-3-319-45307-1_6, (125-158), . LIU H, HUA N, XIE K, ZHAO T and YU Y (2015)(2015) Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury, Molecular Medicine Reports, 10.3892/mmr.2015.3731, 12:2, (2495-2502), Online publication date: 1-Aug-2015. Martire S, Mosca L and d'Erme M (2015) PARP-1 involvement in neurodegeneration: A focus on Alzheimer's and Parkinson's diseases, Mechanisms of Ageing and Development, 10.1016/j.mad.2015.04.001, 146-148, (53-64), Online publication date: 1-Mar-2015. Islam B, Habib S, Ahmad P, Allarakha S, Moinuddin and Ali A (2015) Pathophysiological Role of Peroxynitrite Induced DNA Damage in Human Diseases: A Special Focus on Poly(ADP-ribose) Polymerase (PARP), Indian Journal of Clinical Biochemistry, 10.1007/s12291-014-0475-8, 30:4, (368-385), Online publication date: 1-Oct-2015. Baek S, Noh A, Kim K, Akram M, Shin Y, Kim E, Yu S, Majid A and Bae O (2014) Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage, Stroke, 45:8, (2438-2443), Online publication date: 1-Aug-2014. Fatokun A, Dawson V and Dawson T (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities, British Journal of Pharmacology, 10.1111/bph.12416, 171:8, (2000-2016), Online publication date: 1-Apr-2014. Pérez-Torras S, Vidal-Pla A, Cano-Soldado P, Huber-Ruano I, Mazo A and Pastor-Anglada M (2013) Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner, Cell Death & Disease, 10.1038/cddis.2013.173, 4:5, (e648-e648), Online publication date: 1-May-2013. Virág L, Robaszkiewicz A, Rodriguez-Vargas J and Oliver F (2013) Poly(ADP-ribose) signaling in cell death, Molecular Aspects of Medicine, 10.1016/j.mam.2013.01.007, 34:6, (1153-1167), Online publication date: 1-Dec-2013. Xu H, Luo P, Zhao Y, Zhao M, Yang Y, Chen T, Huo K, Han H and Fei Z (2013) Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos), Cellular Signalling, 10.1016/j.cellsig.2013.01.006, 25:4, (1018-1026), Online publication date: 1-Apr-2013. Abd Elmageed Z, Naura A, Errami Y and Zerfaoui M (2012) The Poly(ADP-ribose) polymerases (PARPs): New roles in intracellular transport, Cellular Signalling, 10.1016/j.cellsig.2011.07.019, 24:1, (1-8), Online publication date: 1-Jan-2012. Bahmani P, Schellenberger E, Klohs J, Steinbrink J, Cordell R, Zille M, Müller J, Harhausen D, Hofstra L, Reutelingsperger C, Farr T, Dirnagl U and Wunder A (2011) Visualization of Cell Death in MICE with Focal Cerebral Ischemia using Fluorescent Annexin A5, Propidium Iodide, and Tunel Staining, Journal of Cerebral Blood Flow & Metabolism, 10.1038/jcbfm.2010.233, 31:5, (1311-1320), Online publication date: 1-May-2011. Egi Y, Matsuura S, Maruyama T, Fujio M, Yuki S and Akira T (2011) Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia, Brain Research, 10.1016/j.brainres.2011.03.031, 1389, (169-176), Online publication date: 1-May-2011. Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H and Takeuchi T (2010) Constitutive Reactive Oxygen Species Generation from Autophagosome/Lysosome in Neuronal Oxidative Toxicity, Journal of Biological Chemistry, 10.1074/jbc.M109.053058, 285:1, (667-674), Online publication date: 1-Jan-2010. WANG L, ZHANG L and SHAN C (2011) A new form of cell death: Parthanatos, Hereditas (Beijing), 10.3724/SP.J.1005.2010.01187, 32:9, (881-885), Online publication date: 12-Jan-2011. Nilsson G (2010) Introduction: why we need oxygen Respiratory Physiology of Vertebrates, 10.1017/CBO9780511845178.002, (3-13) WANG L, ZHANG L and SHAN C (2011) A new form of cell death: Parthanatos, Hereditas (Beijing), 10.3724/SP.J.1005.2010.00881, 32:9, (881-885), Online publication date: 12-Jan-2011. Schultheisz H, Szymczyna B and Williamson J (2009) Enzymatic Synthesis and Structural Characterization of 13 C, 15 N-Poly(ADP-ribose) , Journal of the American Chemical Society, 10.1021/ja903155s, 131:40, (14571-14578), Online publication date: 14-Oct-2009. Wang Y, Dawson V and Dawson T (2009) Poly(ADP-ribose) signals to mitochondrial AIF: A key event in parthanatos, Experimental Neurology, 10.1016/j.expneurol.2009.03.020, 218:2, (193-202), Online publication date: 1-Aug-2009. Eros K, Magyar K, Deres L, Skazel A, Riba A, Vamos Z, Kalai T, Gallyas F, Sumegi B, Toth K, Halmosi R and Bader M (2017) Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats, PLOS ONE, 10.1371/journal.pone.0174401, 12:3, (e0174401) February 2008Vol 39, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.107.511857PMID: 18187674 Manuscript receivedDecember 5, 2007Manuscript acceptedDecember 6, 2007Originally publishedJanuary 10, 2008 Keywordscell deathapoptosisPDF download Advertisement
Referência(s)