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Long-lasting neuronal apoptotic cell death in regions with severe ischemia after photothrombotic ring stroke in rats
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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2002 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 5, p. 462-70Article in journal (Refereed) Published
Abstract [en]

Apoptotic and necrotic cell death may act in concert in focal cerebral ischemia. This study explored the temporal and spatial pattern of apoptosis and necrosis in a novel photothrombotic ring stroke model with or without spontaneous reperfusion. Adult male Wistar rats were subjected to a ring-shaped laser irradiation beam simultaneously with intravenous erythrosin B infusion. The presence and attributes of apoptosis and necrosis in the anatomically well-defined cortical region at risk and ring-lesion region were verified under light microscopy with TUNEL, Hoechst 33342, and hematoxylin and eosin staining. Cells exhibiting apoptotic morphology with chromatin condensation and apoptotic bodies and necrotic ghost appearance were observed. The occurrence of apoptosis and necrosis in the ischemic regions was confirmed by electron microscopy and gel electrophoresis, in which DNA isolated from the lesion area revealed both a ladder and a smear. Double staining with TUNEL and the cell markers NeuN, glial fibrillary acidic protein, and ED-1 revealed that the majority of apoptotic cells were of neuronal origin. Cells exhibiting pyknosis/eosinophilia, apoptosis, or ghost appearance were quantified by stereological means. In subregions with severe ischemia, the peak appearance of apoptotic cells started earlier, i.e., at 24 h, than the peak of necrotic cells, and the high concentration of the apoptotic cells remained as long as that of necrotic cells, i.e., until 72 h post-ischemia. The ratio of apoptotic to necrotic cells was approximately 1:2. Therefore, apoptosis may be an important contributor to neuronal cell death in brain regions with severely reduced blood flow after thrombo-embolic stroke.

Place, publisher, year, edition, pages
Springer, 2002. Vol. 104, no 5, p. 462-70
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-133946DOI: 10.1007/s00401-002-0579-8ISI: 000178750700004PubMedID: 12410394OAI: oai:DiVA.org:umu-133946DiVA, id: diva2:1090135
Available from: 2017-04-22 Created: 2017-04-22 Last updated: 2019-03-19Bibliographically approved
In thesis
1. Apoptotic and necrotic cell death after photothrombotic ring stroke: characterization of a stroke model and its morphological and molecular consequences
Open this publication in new window or tab >>Apoptotic and necrotic cell death after photothrombotic ring stroke: characterization of a stroke model and its morphological and molecular consequences
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cerebral ischemic cell death is a major cause of disability and death among stroke patients. The brain cell demise can occur through apoptosis or necrosis or as a continuum of both. This study aimed at establishing a dual setup of a photothrombotic ring stroke model and exploring its morphological and molecular consequences.

    Photothrombotic ring stroke was induced in adult male Wistar rats by a ring shaped laser irradiation beam (514.5nm, outer diameter 5mm, thickness 0.35 mm) for 120 seconds focused on the exposed intact skull bone with simultaneous intravenous infusion of the photosensitizer erythrosin B (17 mg/kg). By using otherwise identical experimental conditions, high intensity irradiation (1.94 W/cm2) resulted in consistent lack of reperfusion in the region at risk whereas low intensity irradiation (0.90 W/cm2) induced late spontaneous reperfusion. The morphological appearance of apoptotic and necrotic cells was demonstrated by H&E, TUNEL and Hoechst stainings under light microscopy, immunohistochemistry and electron microscopy. This was further confirmed by gel electrophoresis showing DNA laddering that coexisted with DNA smear. Cell counts revealed that apoptotic cells appeared earlier (at 24 h) and remained as long as the necrotic cells, that is up to 72 hours after ischemic onset in regions with severe CBF reduction. After low intensity irradiation, we observed early and widespread increased expression of the anti-apoptotic protein bcl-w and a prolonged elevation of Bcl-2 with unchanged pro-apoptotic Bax in mitochondria. In contrast, decreased bcl-w and Bcl-2 with scattered Bax remained after high intensity irradiation. Correspondingly, the release of the pro-apoptotic factor Smac/DIABLO from the mitochondria to the cytosol was more persistent in high- compared with low-intensity irradiation.   

    Apoptotic and necrotic cell death coexisted in the same regions at the same time after photothrombotic ring stroke induced by low- or high-intensity irradiation, where spontaneous morphological recovery or pannecrosis were evident in the region at risk. The ratios between Bcl-w, Bcl-2 and Bax may direct the translocation of Smac/DIABLO from the mitochondria to the cytosol and thereby influence cell death or survival after focal cerebral ischemia.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2003. p. 59
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 826
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:umu:diva-133950 (URN)91-7305-390-2 (ISBN)
Public defence
2003-02-28, Sal B, plan 9, By 1D, NUS, Umeå, 13:00 (English)
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Supervisors
Available from: 2019-03-19 Created: 2017-04-22 Last updated: 2019-03-21Bibliographically approved

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Hu, XiaoLeiBrännström, ThomasOlsson, TommyWester, Per

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