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01-10-2009 | Original Paper

Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke

Authors: Tiina Sairanen, Rita Szepesi, Marja-Liisa Karjalainen-Lindsberg, Jani Saksi, Anders Paetau, Perttu J. Lindsberg

Published in: Acta Neuropathologica | Issue 4/2009

Abstract

Apoptotic cell death contributes to neuronal loss in the penumbral region of brain infarction. Activated caspase-3 (ACA-3) cleaves proteins including poly(ADP-ribose) polymerase-1 (PARP-1) important in DNA repair, thus promoting apoptosis. Overactivation of PARP-1 depletes NAD⁺ and ATP, resulting in necrosis. These cell death phenomena have been investigated mostly in experimental animals. We studied an autopsy cohort of 13 fatal ischemic stroke cases (symptoms 15 h to 18 days) and 2 controls by immunohistochemical techniques. The number of PARP-1 immunoreactive neurons was highest in the periinfarct area. Nuclear PARP-1 correlated with increasing neuronal necrosis (P = 0.013). Cytoplasmic PARP-1 correlated with TUNEL in periinfarct and core areas (P = 0.01). Cytoplasmic cleaved PARP-1 was inversely correlated with increasing necrotic damage (P = 0.001). PAR-polymers were detected in neurons confirming enzymatic activity of PARP-1. Cytoplasmic ACA-3 correlated with death receptor Fas (r _s = 0.48; P = 0.005). In conclusion, the confirmation of the same pathways of cell death than previously described in experimental animal models encourages neuroprotective treatments acting on these mediators also in human stroke.

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Andrabi SA, Kim NS, Yu S et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103:18308–18318PubMedCrossRef

Ang BT, Yap E, Lim J et al (2003) Poly(adenosine diphosphate-ribose) polymerase expression in human traumatic brain injury. J Neurosurg 99:125–130PubMedCrossRef

Chiarugi A (2005) Poly(ADP-ribosyl)ation and stroke. Pharmacol Res 52:15–24PubMedCrossRef

Chu X, Fu X, Zou L et al (2007) Oncosis, the possible cell death pathway in astrocytes after focal cerebral ischemia. Brain Res 1149:157–164PubMedCrossRef

Cookson MR, Ince PG, Usher PA, Shaw PJ (1999) Poly(ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human CNS neurons. Brain Res 834(1–2):182–185PubMedCrossRef

del Zoppo GJ (2006) Stroke and neurovascular protection. N Engl J Med 354(6):553–555PubMedCrossRef

Desnoyers S, Kaufmann SH, Poirier GG (1996) Alteration of the nucleolar localization of poly(ADP-ribose) polymerase upon treatment with transcription inhibitors. Exp Cell Res 227:146–153PubMedCrossRef

Donnan GA (2008) The 2007 Feinberg lecture. A new road map for neuroprotection. Stroke 39:242–248PubMedCrossRef

Durukan A, Tatlisumak T (2007) Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 87:179–197PubMedCrossRef

10.

Eke A, Conger KA, Anderson M, Garcia JH (1990) Histologic assessment of neurons in rat models of cerebral ischemia. Stroke 21:299–304PubMed

11.

Faden AI, Stoica B (2007) Neuroprotection: challenges and opportunities. Arch Neurol 64(6):794–800PubMedCrossRef

12.

Fakan S, Leduc Y, Lamarre D, Brunet G, Poirier GG (1988) Immunoelectron microscopical distribution of poly(ADP-ribose)polymerase in the mammalian cell nucleus. Exp Cell Res 179(2):517–526PubMedCrossRef

13.

Ferrer I, Planas AM (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62(4):329–339PubMed

14.

Fisher M, Davalos A, Rogalewski A, Schneider A, Ringelstein EB, Schäbitz W (2006) Toward a multimodal neuroprotective treatment of stroke. Stroke 37:1129–1136CrossRef

15.

Graziani G, Battaini F, Zhang J (2005) PARP-1 inhibition to treat cancer, ischemia, inflammation. Pharmacol Res 52:1–4PubMedCrossRef

16.

Graziani G, Szabo C (2005) Clinical perspectives of PARP inhibitors. Pharmacol Res 52:109–118PubMedCrossRef

17.

Guglielmo MA, Chan PT, Cortez S et al (1998) The temporal profile and morphological features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis. Neurol Res 20(4):283–296PubMed

18.

Ha HC, Snyder SH (2000) Poly(ADP-ribose) Polymerase-1 in the nervous system. Neurobiol Dis 7:225–239PubMedCrossRef

19.

Koh DW, Dawson TM, Dawson VL (2005) Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res 52(1):5–14PubMedCrossRef

20.

Love S, Barber R, Srinivasan A, Wilcock GK (2000) Activation of caspase-3 in permanent and transient brain ischemia in man. NeuroReport 11:2495–2499PubMedCrossRef

21.

Love S, Barber R, Wilcock GK (2000) Neuronal death in brain infarcts in man. Neuropath Appl Neurobiol 26:55–66CrossRef

22.

McLaughlin B (2004) The kinder side of killer proteases: caspase activation contributes to neuroprotection and CNS remodeling. Apoptosis 9(2):111–121PubMedCrossRef

23.

Meder VS, Boeglin M, de Murcia G, Schreiber V (2005) PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. J Cell Sci 118(1):211–222PubMedCrossRef

24.

Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54:34–66PubMedCrossRef

25.

Meli E, Pangallo M, Baronti R et al (2003) Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol Lett 139:153–162PubMedCrossRef

26.

Mitsios N, Gaffney J, Krupinski J et al (2007) Expression of signaling molecules associated with apoptosis in human stroke tissue. Cell Biochem Biophys 47(1):73–86PubMed

27.

Moroni F (2007) Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr Opin Pharmacol 7:1–8CrossRef

28.

Pacher P, Szabo C (2008) Role of the peroxynitrite-poly(ADP-Ribose) polymerase pathway in human disease. Am J Pathol 173(1):2–13PubMedCrossRef

29.

Rami A, Bechmann I, Stehle JH (2008) Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia. Prog Neurobiol 85(3):273–296PubMedCrossRef

30.

Sairanen T, Karjalainen-Lindsberg M, Paetau A, Ijäs P, Lindsberg PJ (2006) Apoptosis dominant in the periinfarct area of human ischemic stroke—a possible target of antiapoptotic treatments. Brain 129:189–199PubMedCrossRef

31.

Solaroglu I, Tsubokawa T, Cahill J, Zhang JH (2006) Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience 143(4):965–974PubMedCrossRef

32.

Soldani C, Lazzè MC, Bottone MG et al (2001) Poly(ADP-ribose) polymerase cleavage during apoptosis: when and where? Exp Cell Res 269(2):193–201PubMedCrossRef

33.

Stadelmann D, Mews I, Srinivasan A, Deckwerth TL, Lassmann H, Bruck W (2001) Expression of cell death-associated proteins in neuronal apoptosis associated with pontosubicular neuron necrosis. Brain Pathol 11(3):273–281CrossRef

34.

Szabo C, Pacher P, Swanson RA (2006) Novel modulators of poly(ADP-ribose)polymerase. Trends Pharmacol Sci 27:626–630PubMedCrossRef

35.

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(14):5932–5941PubMed

36.

Yu S, Wang H, Poitras MF et al (2002) Mediation of Poly(ADP-Ribose) Polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297

Title: Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke
Authors: Tiina Sairanen
Rita Szepesi
Marja-Liisa Karjalainen-Lindsberg
Jani Saksi
Anders Paetau
Perttu J. Lindsberg
Publication date: 01-10-2009
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 4/2009
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-009-0559-3

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Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke

Abstract

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