scholarly journals Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke

1997 ◽  
Vol 2 (5) ◽  
pp. E3 ◽  
Author(s):  
Ahmed Rawanduzy ◽  
Anker Hansen ◽  
Thomas W. Hansen ◽  
Maiken Nedergaard
Keyword(s):  
Gap Junction ◽  
Spreading Depression ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Histopathological Analysis ◽  
Infarction Volume ◽  
Effective Reduction ◽  
Lines Of Evidence ◽  
Over Time

Several lines of evidence indicate that the extent of ischemic injury is not defined immediately following arterial occlusion; rather that infarction expands over time. Episodes of spreading depression have been linked to this secondary increase in infarct volume. Tissue bordering the infarct fails to repolarize following spreading depression and is incorporated into the infarction. The result is that ischemic infarcts expand stepwise following each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively inhibit spreading depression. These observations suggest that the efflux of potentially harmful cytosolic messengers from ischemic cells into surrounding nonischemic cells might cause amplification of injury in focal stroke. It is therefore conceivable that minimizing gap junction permeability might reduce final infarct volume. To test this hypothesis, the authors pretreated rats with the gap junction blocker, octanol, before occluding the middle cerebral artery and compared the sizes of the ischemic lesions to those in rats that received vehicle dimethyl sulfoxide prior to arterial occlusion. Histopathological analysis was performed 24 hours later. The 12 octanol-treated animals showed a significantly decreased mean infarction volume (80 ± 16 mm3) compared with the nine control rats (148 ± 9 mm3). In a separate set of experiments, the frequency of experimentally induced waves of spreading depression was evaluated following octanol treatment. Octanol pretreatment resulted in complete inhibition in two of nine animals, transient inhibition in five of nine, and no inhibition in two of nine. The results indicate that gap junction inhibitors, when not limited by toxicity, have significant therapeutic potential in the treatment of acute stroke.

Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke

1997 ◽  
Vol 87 (6) ◽  
pp. 916-920 ◽  
Author(s):  
Ahmed Rawanduzy ◽  
Anker Hansen ◽  
Thomas W. Hansen ◽  
Maiken Nedergaard
Keyword(s):  
Gap Junction ◽  
Spreading Depression ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Histopathological Analysis ◽  
Content Type ◽  
Infarction Volume ◽  
Effective Reduction ◽  
Fine Print

✓ Several lines of evidence indicate that the extent of ischemic injury is not defined immediately after arterial occlusion, but that infarction expands over time. Episodes of spreading depression have been linked to this secondary increase in infarct volume. Tissue bordering the infarction fails to repolarize following spreading depression and is incorporated into the lesion. The result is that ischemic infarctions expand stepwise after each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively inhibit spreading depression. These observations suggest that traffic of potentially harmful cytosolic messengers between ischemic cells and surrounding nonischemic cells might cause amplification of injury in focal stroke. It is therefore conceivable that minimizing gap junction permeability might reduce final infarct volume. To test this hypothesis, the authors pretreated rats with the gap junction blocker, octanol, before occluding the middle cerebral artery and compared the sizes of the ischemic lesions to those in rats that received the vehicle, dimethyl sulfoxide, prior to arterial occlusion. Histopathological analysis was performed 24 hours later. The 12 octanol-treated animals showed a significantly decreased mean infarction volume (80 ± 16 mm3) compared with the nine control rats (148 ± 9 mm3). In a separate set of experiments, the frequency of experimentally induced waves of spreading depression was evaluated after octanol treatment. Octanol pretreatment resulted in complete inhibition in two of nine animals, transient inhibition in five, and no inhibition in two. The results indicate that gap junction inhibitors, when not limited by toxicity, have significant therapeutic potential in the treatment of acute stroke.

Abstract 3851: Temporal Distribution of Stroke Volumes and Clinical-Diffusion Mismatch in Patients with Proximal Arterial Occlusions

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Raul G Nogueira ◽  
David S Liebeskind ◽  
Leticia M Souza ◽  
Qing Hao ◽  
Karen Furie ◽  
...  
Keyword(s):  
Linear Regression ◽  
Infarct Volume ◽  
Linear Regression Analysis ◽  
Significant Proportion ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Poor Correlation ◽  
Lesion Volume ◽  
Collateral Flow ◽  
Over Time

Background and Purpose: Previous studies have demonstrated that the benefit of reperfusion therapy declines over time. The Clinical-Diffusion Mismatch (CDM) model has been suggested as surrogate for salvable tissue in acute ischemic stroke (AIS) patients. We sought to describe the temporal behavior profile of infarct volumes and CDM in patients suffering AIS due to proximal arterial occlusion (PAO). Methods: We performed a retrospective analysis of consecutive AIS patients admitted to two large academic institutions fulfilling the following criteria: (1) Baseline NIHSS ≥8; (2) PAO defined as MCA-M1, intracranial ICA, or tandem cervical + ICA/MCA-M1 occlusion on admission CTA/MRA; and (3) MRI-DWI performed ≤8 hours from time of stroke onset/last seen well (TSO). CDM was defined as baseline NIHSS ≥8 and DWI volume ≤25cc (as proposed by Davalos et al). Linear regression analysis was performed to define the changes on DWI lesion volume on presentation over time. The observed TSO to MRI were broken down into quartiles to look for any differences in the distribution of the baseline variables over time. Results: A total of 132 consecutive patients were identified (mean age, 66±16.8 years; 57% females; mean baseline NIHSS 17.5±5.3; occlusion site: MCA-M1, 64%; intracranial-ICA, 29%; tandem, 5%, mean TSO to DWI, 269.5±105.48 minutes). The mean DWI stroke volume on presentation was 46.7±54.8 cc (range, 0.19-436.1) and 63 (46.7%) patients had CDM. There was no significant changes in age, gender, baseline NIHSS, or occlusion site amongst the different time quartiles. Median infarct volume (cc) increased (quartile #1=8.5; #2=30.1; #3=38.5; #4=29.4) and the chances of having a CDM decreased (p<0.0001) across the different time quartiles. However, there was an overall poor correlation between DWI lesion volume on presentation and TSO to MRI (R-square=0.031, Figure ) and a significant proportion of the patients still had a CDM at later time epochs (#1=91.1%[20/22]; #2=47.8%[11/23]; #3=34.4%[21/61]; #4=42.3%[11/26]). Conclusions: Although infarct volume increases and the amount of penumbral tissue decreases over time, many patients with PAO will still have salvable penumbra at the later time epochs. This reflects individual differences in anatomic and physiological characteristics including the strength of collateral flow and highlights that selected patients may benefit from reperfusion therapy even at the later time windows. Figure : Relationship between Baseline DWI Volume (cc) and Time (minutes). Line is best fitted linear regression model.

scholarly journals Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 353 ◽  
Author(s):  
Moises Freitas-Andrade ◽  
John Bechberger ◽  
Jasmine Wang ◽  
Ken Yeung ◽  
Shawn Whitehead ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Imaging Mass Spectrometry ◽  
Arterial Occlusion ◽  
Maldi Ims ◽  
Junctional Coupling ◽  
Stroke Models ◽  
Gap Junctional Coupling

Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential target for therapeutic approaches to stroke. We examined the effect of danegaptide (ZP1609), an antiarrhythmic dipeptide that specifically enhances GJ conductance, in two different rodent stroke models. In this study, danegaptide increased astrocytic Cx43 coupling with no significant effects on Cx43 hemichannel activity, in vitro. Using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) the presence of danegaptide within brain tissue sections were detected one hour after reperfusion indicating successful transport of the dipeptide across the blood brain barrier. Furthermore, administration of danegaptide in a novel mouse brain ischemia/reperfusion model showed significant decrease in infarct volume. Taken together, this study provides evidence for the therapeutic potential of danegaptide in ischemia/reperfusion stroke.

scholarly journals The Uses and Abuses of Tree Thinking in Cultural Evolution

2021 ◽  
Author(s):  
Cara Evans ◽  
Simon J. Greenhill ◽  
Joseph Watts ◽  
Johann-Mattis List ◽  
Carlos A. Botero ◽  
...  
Keyword(s):  
Best Practices ◽  
Cultural Evolution ◽  
Cross Cultural ◽  
Tree Thinking ◽  
Phylogenetic Methods ◽  
Cultural Research ◽  
Cross Cultural Research ◽  
Cultural Traits ◽  
Lines Of Evidence ◽  
Over Time

Modern phylogenetic methods are increasingly being used to address questions about macro-level patterns in cultural evolution. These methods can illuminate the unobservable histories of cultural traits and identify the evolutionary drivers of trait-change over time, but their application is not without pitfalls. Here we outline the current scope of research in cultural tree thinking, highlighting a toolkit of best practices to navigate and avoid the pitfalls and ‘abuses’ associated with their application. We emphasise two principles that support the appropriate application of phylogenetic methodologies in cross-cultural research: researchers should (1) draw on multiple lines of evidence when deciding if and which types of phylogenetic methods and models are suitable for their cross-cultural data, and (2) carefully consider how different cultural traits might have different evolutionary histories across space and time. When used appropriately phylogenetic methods can provide powerful insights into the processes of evolutionary change that have shaped the broad patterns of human history.

scholarly journals Cortical Spreading Depression Protects against Subsequent Focal Cerebral Ischemia in Rats

1996 ◽  
Vol 16 (2) ◽  
pp. 221-226 ◽  
Author(s):  
Kazushi Matsushima ◽  
Matthew J. Hogan ◽  
Antoine M. Hakim
Keyword(s):  
Cerebral Ischemia ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Occipital Cortex ◽  
Artery Occlusion ◽  
Microdialysis Probe ◽  
Cerebral Artery Occlusion ◽  
Subcortical Infarct

The possibility that cortical spreading depression (CSD) may have neuroprotective action during subsequent focal cerebral ischemia was examined in rats. Three days before the imposition of focal cerebral ischemia CSDs were elicited by applying potassium chloride (KCl) for 2 h through a microdialysis probe implanted in the occipital cortex. Control animals were handled identically except that saline was infused instead of KCl. Focal ischemia was produced by the intraluminal suture method and cortical and subcortical infarct volumes were measured 7 days later. Neocortical infarct volume was reduced from 124.8 ± 49.5 mm3 in the controls to 62.9 ± 59.5 mm3 in the animals preconditioned with CSD (p = 0.012). There was no difference between the two groups in the subcortical infarct volume or in CBF, measured by the hydrogen clearance method, during or immediately after the ischemic interval. Our data indicate that preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brain's resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells.

Cerebral protection by intermittent reperfusion during temporary focal ischemia in the rat

1996 ◽  
Vol 85 (5) ◽  
pp. 923-928 ◽  
Author(s):  
Carlos A. David ◽  
Ricardo Prado ◽  
W. Dalton Dietrich
Keyword(s):  
Arterial Occlusion ◽  
Focal Ischemia ◽  
Global Ischemia ◽  
Cerebral Injury ◽  
Histopathological Analysis ◽  
Content Type ◽  
Group I ◽  
Group Ii ◽  
Temporary Clipping ◽  
Fine Print

✓ Temporary arterial occlusion has been routinely used as an adjunct in intracranial aneurysm surgery. This has commonly been performed using a protocol of multiple short periods of occlusion alternating with periods of restoration of normal circulation. Recently, the logical basis of this method has come under scrutiny. There is extensive experimental evidence to suggest that repetitive, brief periods of global ischemia may cause more severe cerebral injury than an equivalent single period of global ischemia. Only recently has this issue begun to be addressed with regard to focal ischemia. Hence, despite the common use of temporary clipping, little experimental data are available regarding the ischemic consequences of temporary arterial occlusion with periods of reperfusion versus uninterrupted temporary occlusion. To investigate this issue, a protocol of occlusion/reperfusion that simulates the temporal profile that occurs during surgery was performed in a rat model of focal ischemia. Sixteen anesthetized Sprague—Dawley rats were divided into two groups. The animals in Group I underwent 60 minutes of uninterrupted middle cerebral artery occlusion and the animals in Group II were subjected to six separate 10-minute occlusion periods with 5 minutes of reperfusion between occlusions. Histopathological analysis was performed 72 hours postischemia. Group I had significantly increased mean infarction volumes (50.0 ± 12.1 mm3) compared to Group II (8.7 ± 3.1 mm3) (p = 0.008). Injuries in Group I occurred in both the cortex and striatum, whereas Group II showed only striatal injuries. Furthermore, the extent of the injuries in Group II was less severe, characterized by ischemic neuronal injury rather than frank infarction. The results indicate that intermittent reperfusion is neuroprotective during temporary focal ischemia and support the hypothesis that intermittent reperfusion is beneficial if temporary clipping is required during aneurysm repair.

Changes in hematological, hemostatic and biochemical parameters induced experimentally in rabbits by Loxosceles gaucho spider venom

2004 ◽  
Vol 23 (10) ◽  
pp. 477-486 ◽  
Author(s):  
Flávio Luiz Tavares ◽  
Maria Cristina Cirillo Sousa-e-Silva ◽  
Marcelo Larami Santoro ◽  
Káitia Cristina Barbaro ◽  
Ivanise Marina Moretti Rebecchi ◽  
...  
Keyword(s):  
Biochemical Parameters ◽  
Coagulation Factors ◽  
Histopathological Analysis ◽  
Intravascular Hemolysis ◽  
Blood Cell Count ◽  
Total Blood ◽  
Systemic Reactions ◽  
Coagulation Tests ◽  
Platelet Hyperaggregation ◽  
Over Time

Human accidents caused by Loxosceles spiders may result in local dermal necrosis and, in some cases, severe systemic reactions - such as intravascular hemolysis, disseminated intravascular coagulation (DIC), renal failure and death. Since many aspects of envenomation by Loxosceles spiders remain unclear, we studied the hematological and hemostatic responses induced by the i.d. injection of 10 μg/kg Loxosceles gaucho venom in rabbits. For this purpose, total blood cell count, platelet function, coagulation tests and biochemical parameters were analysed at 3, 24, 48, 72 and 120 hours after venom administration. Thrombocytopenia and leukopenia were noted at 3 and 24 hours. Histopathological analysis of the skin lesion, performed at 24 hours after venom administration, showed a massive presence of leukocytes and platelets, hemorrhage and thrombus fornation at the injection site. At 72 and 120 hours, neutrophilic leukocytosis and thrombocytosis were observed. Platelet hyperaggregation was noticeable at 48 and 72 hours. Haptoglobin and fibrinogen levels were elevated early and remained in high levels over time. Significant increases in coagulation factors V, VII, VIII, IX, X and XI were noted at 120 hours. The results showed that neither intravascular hemolysis nor DIC occurred. However, the early onset of thrombocytopenia and leukopenia are important findings that may be related to dermal necrosis formation during loxoscelism.

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