Neuronal caspase-3 and PARP-1 correlate differentially with apoptosis and necrosis in ischemic human stroke.
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.
Sairanen
Tiina
T
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. tiina.sairanen@hus.fi
Szepesi
Rita
R
Karjalainen-Lindsberg
Marja-Liisa
ML
Saksi
Jani
J
Paetau
Anders
A
Lindsberg
Perttu J
PJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D002452:Cell Count; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3