Erratum to: Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke

To determine the occurrence and time-course of presumably irreversible subcellular damage after moderate focal ischemia, rats were subjected to 1, 3, 6, 9, or 24 hours of permanent unilateral middle cerebral and common carotid occlusion or 3 hours of reversible occlusion followed by 3, 6, or 21 hours of reperfusion. The topography and the extent of damage were analyzed with tetrazolium staining and immunoblot using an antibody capable of detecting breakdown of neurofilament. Neurofilament proteolysis began after 3 hours in the infarct core but was still incomplete in penumbral regions up to 9 hours. Similarly, tetrazolium-staining abnormalities were observed in the core of 50% of animals after 3 hours of ischemia. At 6 hours of permanent ischemia, infarct volume was maximal, and further prolongation of occlusion to 9 or 24 hours did not increase abnormal tetrazolium staining. In contrast to permanent ischemia and in agreement with the authors' previous demonstration of “reperfusion injury” in this model, prolongation of reperfusion from 3 hours to 6 and 21 hours after 3 hours of reversible occlusion gradually augmented infarct volume by 203% and 324%, respectively. Neurofilament proteolysis initiated approximately 3 hours after ischemia was quantitatively greatest in the core and extended during reperfusion to incorporate penumbra with a similar time course to that of tetrazolium abnormalities. These data demonstrate that, at least as measured by neurofilament breakdown and mitochondrial failure, extensive cellular damage is not present in penumbral regions for up to 9 hours, suggesting the potential for rescuing these regions by appropriate and timely neuroprotective strategies.

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Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke

Advanced Science ◽

10.1002/advs.202101433 ◽

2021 ◽

pp. 2101433

Author(s):

Violaine Hubert ◽

Ines Hristovska ◽

Szilvia Karpati ◽

Sarah Benkeder ◽

Arindam Dey ◽

...

Keyword(s):

Multimodal Imaging ◽

Experimental Stroke ◽

Spatiotemporal Features

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Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

Translational Stroke Research ◽

10.1007/s12975-021-00923-3 ◽

2021 ◽

Author(s):

Leoni Rolfes ◽

Tobias Ruck ◽

Christina David ◽

Stine Mencl ◽

Stefanie Bock ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Adoptive Transfer ◽

Immune Cell ◽

Nk Cell ◽

Cell Subset ◽

Neurological Deficits ◽

In Vitro Assays ◽

Experimental Stroke ◽

Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

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Temporal and spatial gene expression patterns after experimental stroke in a rat model and characterization of PC4, a potential regulator of transcription

Molecular and Cellular Neuroscience ◽

10.1016/s1044-7431(02)00039-8 ◽

2003 ◽

Vol 22 (3) ◽

pp. 353-364 ◽

Cited By ~ 31

Author(s):

Adrian Roth ◽

Ramanjit Gill ◽

Ulrich Certa

Keyword(s):

Gene Expression ◽

Rat Model ◽

Expression Patterns ◽

Experimental Stroke ◽

Gene Expression Patterns ◽

Temporal And Spatial

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Intravenous Injection of Clinical Grade Human MSCs after Experimental Stroke: Functional Benefit and Microvascular Effect

Cell Transplantation ◽

10.3727/096368916x691132 ◽

2016 ◽

Vol 25 (12) ◽

pp. 2157-2171 ◽

Cited By ~ 12

Author(s):

Anaïck Moisan ◽

Isabelle Favre ◽

Claire Rome ◽

Florence De Fraipont ◽

Emmanuelle Grillon ◽

...

Keyword(s):

Transforming Growth Factor ◽

Ex Vivo ◽

Quantitative Polymerase Chain Reaction ◽

Transforming Growth Factor Β1 ◽

Angiogenic Factors ◽

Experimental Stroke ◽

Vascular Density ◽

Human Mscs ◽

Functional Benefit

Stroke is the leading cause of disability in adults. Many current clinical trials use intravenous (IV) administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs). This autologous graft requires a delay for ex vivo expansion of cells. We followed microvascular effects and mechanisms of action involved after an IV injection of human BM-MSCs (hBM-MSCs) at a subacute phase of stroke. Rats underwent a transient middle cerebral artery occlusion (MCAo) or a surgery without occlusion (sham) at day 0 (D0). At D8, rats received an IV injection of 3 million hBM-MSCs or PBS-glutamine. In a longitudinal behavioral follow-up, we showed delayed somatosensory and cognitive benefits 4 to 7 weeks after hBM-MSC injection. In a separate longitudinal in vivo magnetic resonance imaging (MRI) study, we observed an enhanced vascular density in the ischemic area 2 and 3 weeks after hBM-MSC injection. Histology and quantitative polymerase chain reaction (qPCR) revealed an overexpression of angiogenic factors such as Ang1 and transforming growth factor-β1 (TGF-β1) at D16 in hBM-MSC-treated MCAo rats compared to PBS-treated MCAo rats. Altogether, delayed IV injection of hBM-MSCs provides functional benefits and increases cerebral angiogenesis in the stroke lesion via a release of endogenous angiogenic factors enhancing the stabilization of newborn vessels. Enhanced angiogenesis could therefore be a means of improving functional recovery after stroke.

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Speed of motor re-learning after experimental stroke depends on prior skill

Experimental Brain Research ◽

10.1007/s00221-007-0930-3 ◽

2007 ◽

Vol 181 (2) ◽

pp. 359-365 ◽

Cited By ~ 13

Author(s):

Maximilian Schubring-Giese ◽

Katiuska Molina-Luna ◽

Benjamin Hertler ◽

Manuel M. Buitrago ◽

Daniel F. Hanley ◽

...

Keyword(s):

Experimental Stroke

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Abstract WP281: Incorporating Biological Variability in Experimental Stroke to Better Mimic Human Stroke

Stroke ◽

10.1161/str.48.suppl_1.wp281 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Thomas A Kent ◽

Harriett C Rea ◽

William Dalmeida ◽

Roderic H Fabian ◽

Cenk Ayata ◽

...

Keyword(s):

Middle Surface ◽

Lower Surface ◽

Clinical Results ◽

Experimental Stroke ◽

Biological Variability ◽

Occlusion Time ◽

Physiological Variability ◽

Functional Measure ◽

Stroke Models ◽

Human Stroke

Introduction: Failures to translate pre-clinical results have been discouraging. We have contended that stroke is too heterogeneous with respect to factors influencing outcome to expect small studies to be balanced. It is not only difficult to control for biological and methodological variability but efforts to improve homogeneity, such as minimizing physiological variability, may render results less applicable to humans. Here, we report a predictive outcome model in experimental stroke which incorporates baseline variability and provides statistical thresholds a treatment must exceed to be efficacious in a broad population. Methods: We generated a mathematical model to predict outcome using transient MCA occlusion in 23 unfasted rats. To create baseline variability, we varied occlusion times from 90-120 min, altered baseline glucose with streptozotocin, and assessed neurological outcome 3 days later with a modified Bederson Score (BS; 0-6 functional measure, 7 death). Statistical surfaces in 3 dimensions were generated using Jacobian matrices flanking the model to provide a screening threshold (1 SD) for comparing new therapies against this model. Results: We successfully generated an outcome model from occlusion time, glucose and BS (Fig; R 2 =.49, p=.0003; middle surface is the model surrounded by ±SD surfaces). Outcome was sensitive to change in glucose and time, suggesting small imbalances in these factors between groups may influence outcome, and hence the perceived efficacy of a new therapeutic intervention. At normoglycemia and 90 mins, the lower surface overlapped with no deficit, indicating it would be difficult to reliably demonstrate benefit under those conditions. Conclusions: These results indicate it is feasible to incorporate biological variability to generate more clinically relevant conditions. The method will be tested with other stroke models and modifiers towards a generalized model to screen for therapies worthy of further study.

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