Multiple Molecular Penumbras after Focal Cerebral Ischemia

Sharp, Frank R.; Lu, Aiming; Tang, Yang; Millhorn, David E.

doi:10.1097/00004647-200007000-00001

Cited by 376 publications

(313 citation statements)

References 333 publications

(93 reference statements)

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“…However, the majority studies measured gene profiles in the brain cells other than SVZ cells focusing on the acute stage of ischemic stroke (Sharp et al, 2000;Kim et al, 2002;Schmidt-Kastner et al, 2002;Lu et al, 2004;Rickhag et al, 2006). Further studies to identify genes trigged by ischemia specific for neural progenitor cells are warranted.…”

Section: Discussionmentioning

confidence: 99%

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

Liu¹,

Zhang²,

Zhang³

et al. 2006

J Cereb Blood Flow Metab

105

100

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Neural progenitor cells in the subventricular zone (SVZ) of the lateral ventricular wall give rise to new neurons throughout rodent life. Ischemic stroke induces angiogenesis and neurogenesis. Using laser capture microdissection (LCM) in combination with microarrays containing approximately 400 known genes associated with stem cells and angiogenesis, we investigated gene profiles of SVZ cells in the adult mouse subjected to middle cerebral artery occlusion. Our data revealed that nonstroke SVZ cells expressed sets of genes that are important for neural progenitor cell proliferation, differentiation, and migration. In addition, stroke SVZ cells expressed many genes involved in neurogenesis during embryonic development but were not detected in nonstroke SVZ cells. Stroke upregulated genes were verified by real-time reverse transcriptase-polymerase chain reaction and immunostaining. These data indicate that adult SVZ cells recapture embryonic molecular signals after stroke and provide insight into the molecular mechanisms, which regulate the biological function of neural progenitor cells in the SVZ of adult rodent brain under physiological and stroke conditions.

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Section: Discussionmentioning

confidence: 99%

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

Liu¹,

Zhang²,

Zhang³

et al. 2006

J Cereb Blood Flow Metab

105

100

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show abstract

“…31,32 Of note, the areas of tracer extravasation appeared to be neither limited to the zones of enhanced neuronal HSP70 expression, nor to the zones of decreased MAP2 immunoreactivity, but rather exceeded them on the outer border (Supplementary Figure 1). Therefore, the analyzed border zones of tracer extravasation presumably correspond to the outer layers of the ischemic 'penumbra', but not to the ischemic core.…”

Section: Ischemia-induced Blood-brain Barrier Breakdown M Krueger Et Almentioning

confidence: 99%

Blood—Brain Barrier Breakdown Involves Four Distinct Stages of Vascular Damage in Various Models of Experimental Focal Cerebral Ischemia

Krueger

Bechmann

Immig

et al. 2014

J Cereb Blood Flow Metab

184

145

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Ischemic stroke not only impairs neuronal function but also affects the cerebral vasculature as indicated by loss of blood-brain barrier (BBB) integrity. Therefore, therapeutical recanalization includes an enhanced risk for hemorrhagic transformation and bleeding, traditionally attributed to a 'reperfusion injury'. To investigate the mechanisms underlying ischemia-/reperfusion-related BBB opening, we applied multiple immunofluorescence labeling and electron microscopy in a rat model of thromboembolic stroke as well as mouse models of permanent and transient focal cerebral ischemia. In these models, areas exhibiting BBB breakdown were identified by extravasation of intravenously administered fluorescein isothiocyanate (FITC)-albumin. After 24 hours, expression of markers for tight and adherens junctions in areas of FITC-albumin leakage consistently remained unaltered in the applied models. However, lectin staining with isolectin B4 indicated structural alterations in the endothelium, which were confirmed by electron microscopy. While ultrastructural alterations in endothelial cells did not differ between the applied models including the reperfusion scenario, we regularly identified vascular alterations, which we propose to reflect four distinct stages of BBB breakdown with ultimate loss of endothelial cells. Therefore, our data strongly suggest that ischemia-related BBB failure is predominantly caused by endothelial degeneration. Thus, protecting endothelial cells may represent a promising therapeutical approach in addition to the established recanalizing strategies.

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“…This concept was first suggested for the progression of early damage in acute stroke [4] but has even greater meaning in the changes of tissue repair and recovery, such as distinct zones of reactive astrocytes and dendritic spine changes.…”

Section: Radial Stroke: Zones Of Damagementioning

confidence: 99%

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

Carmichael

2016

Neurotherapeutics

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Stroke not only causes initial cell death, but also a limited process of repair and recovery. As an overall biological process, stroke has been most often considered from the perspective of early phases of ischemia, how these inter-relate and lead to expansion of the infarct. However, just as the biology of later stages of stroke becomes better understood, the clinical realities of stroke indicate that it is now more a chronic disease than an acute killer. As an overall biological process, it is now more important to understand how early cell death leads to the later, limited recovery so as develop an integrative view of acute to chronic stroke. This progression from death to repair involves sequential stages of primary cell death, secondary injury events, reactive tissue progenitor responses, and formation of new neuronal circuits. This progression is radial: from the tissue that suffers the infarct secondary injury signals, including free radicals and inflammatory cytokines, radiate out from the stroke core to trigger later regenerative events. Injury and repair processes occur not just in the local stroke site, but are also triggered in the connected networks of neurons that had existed in the stroke center: damage signals are relayed throughout a brain network. From these relayed, distributed damage signals, reactive astrocytosis, inflammatory processes, and the formation of new connections occur in distant brain areas. In short, emerging data in stroke cell death studies and the development of the field of stroke neural repair now indicate a continuum in time and in space of progressive events that can be considered as the 3 Rs of stroke biology: radial, relayed, and regenerative.

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Multiple Molecular Penumbras after Focal Cerebral Ischemia

Cited by 376 publications

References 333 publications

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

Stroke Induces Gene Profile Changes Associated with Neurogenesis and Angiogenesis in Adult Subventricular Zone Progenitor Cells

Blood—Brain Barrier Breakdown Involves Four Distinct Stages of Vascular Damage in Various Models of Experimental Focal Cerebral Ischemia

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

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