Apoptosis dominant in the periinfarct area of human ischaemic stroke—a possible target of antiapoptotic treatments

T Sairanen, ML Karjalainen-Lindsberg, A Paetau, P Ijäs… - Brain, 2006 - academic.oup.com
T Sairanen, ML Karjalainen-Lindsberg, A Paetau, P Ijäs, PJ Lindsberg
Brain, 2006academic.oup.com
Animal experiments have suggested that apoptotic programmed cell death is responsible for
an important portion of the delayed ischaemic brain damage. Antiapoptotic signalling
through erythropoietin (EPO) binding to its receptor (EPOR) is triggered by systemic or local
hypoxia and may exist in the post-ischaemic brain, and a neuroprotective effect by EPO was
described recently and proposed for clinical stroke treatment. The objective of the study was
to determine whether apoptosis occurs in human ischaemic stroke and to describe its …
Abstract
Animal experiments have suggested that apoptotic programmed cell death is responsible for an important portion of the delayed ischaemic brain damage. Antiapoptotic signalling through erythropoietin (EPO) binding to its receptor (EPOR) is triggered by systemic or local hypoxia and may exist in the post-ischaemic brain, and a neuroprotective effect by EPO was described recently and proposed for clinical stroke treatment. The objective of the study was to determine whether apoptosis occurs in human ischaemic stroke and to describe its topographical distribution. An autopsy cohort consisting of 13 cases of fatal ischaemic stroke (symptom duration from 15 h to 18 days) treated at the Department of Neurology, Helsinki University Central Hospital and 3 controls were studied. DNA damage was investigated by immunofluorescent TUNEL-labelling in combination with apoptotic cell morphology and by visualization of a major signalling system of apoptosis, Fas−FasL (Fas-ligand), by the immunoperoxidase technique. The relationship of EPO and EPOR in the face of TUNEL-labelled and necrotic cell death was co-registered in human cerebral neurons undergoing different stages of ischaemic change. TUNEL-labelled cells with apoptotic morphology were disproportionately more frequent, 148% (30) [mean (SE)] in the periinfarct versus 97% (22) in the core, as percentage of the cells in the contralateral hemisphere (P = 0.027). The apoptotic cell percentage reached up to 26% (2) of all cells in periinfarct area. A linear correlation was found for Fas and its counterpart FasL expression (rS = 0.774, P < 0.001). Ischaemia induced widespread neuronal expression of EPOR, which was inversely related to the severity of ischaemic neuronal necrosis (P < 0.05). To conclude, these data verify the predominance of apoptosis in the periphery of human ischaemic infarctions. Fas and FasL were linearly overexpressed supporting that this ‘death-receptor’ complex may promote the completion of cell death. Increased EPO signalling may be a cellular response for survival in less severely damaged areas. These results support antiapoptotic therapies against delayed neuronal cell death in human ischaemic stroke.
Oxford University Press