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

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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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Abbreviations

ACA:

Activated caspase-3

AIF:

Apoptosis inducing factor

PARP-1:

Poly(ADP-Ribose) polymerase-1

TUNEL:

Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling

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Acknowledgments

The study was financially supported by The Finnish Academy, Sigrid Jusélius Foundation, HUCH governmental subsidiary grants for research (EVO), Päivikki and Sakari Sohlberg Foundation, H. Lundbeck Inc., Maire Taponen Foundation, The Finnish Medical Foundation, Finnish Cultural Foundation and Aarne Koskelo Foundation. The authors thank Ms. Tanja Eriksson and Mrs. Taru Puhakka for skillful technical assistance. This study belongs to a series of post-mortem stroke studies designated collectively as the Helsinki Stroke Study (HSS).

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Helsinki University Central Hospital (HUCH), P.O. Box 340, 00029, Helsinki, Finland

    Tiina Sairanen & Perttu J. Lindsberg

  2. Molecular Neurology Program, Biomedicum Helsinki, P.O. Box 700, 00029, Helsinki, Finland

    Tiina Sairanen, Rita Szepesi, Jani Saksi & Perttu J. Lindsberg

  3. Department of Pathology, University of Helsinki, Haartmaninkatu 3, 00029, Helsinki, Finland

    Marja-Liisa Karjalainen-Lindsberg & Anders Paetau

  4. Department of Neurology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Rita Szepesi

Authors
  1. Tiina Sairanen
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  2. Rita Szepesi
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  3. Marja-Liisa Karjalainen-Lindsberg
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  4. Jani Saksi
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  5. Anders Paetau
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  6. Perttu J. Lindsberg
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Corresponding author

Correspondence to Tiina Sairanen.

Additional information

T. Sairanen and R. Szepesi contributed equally to this study.

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Sairanen, T., Szepesi, R., Karjalainen-Lindsberg, ML. et al. Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke. Acta Neuropathol 118, 541–552 (2009). https://doi.org/10.1007/s00401-009-0559-3

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  • DOI: https://doi.org/10.1007/s00401-009-0559-3

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