scholarly journals Different Strokes for Different Folks: The Rich Diversity of Animal Models of Focal Cerebral Ischemia

2010 ◽  
Vol 30 (8) ◽  
pp. 1412-1431 ◽  
Author(s):  
David W Howells ◽  
Michelle J Porritt ◽  
Sarah SJ Rewell ◽  
Victoria O'Collins ◽  
Emily S Sena ◽  
...  
Keyword(s):  
Animal Model ◽  
Ischemic Stroke ◽  
Animal Models ◽  
Focal Cerebral Ischemia ◽  
Experimental Stroke ◽  
Stroke Outcome ◽  
Rich Diversity ◽  
Single Animal ◽  
The Rich ◽  
Use Of Models

No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.

scholarly journals α2-Adrenoceptors do not Mediate Neuroprotection in Acute Ischemic Stroke in Mice

2011 ◽  
Vol 31 (10) ◽  
pp. e1-e7 ◽  
Author(s):  
Marc Brede ◽  
Stefan Braeuninger ◽  
Friederike Langhauser ◽  
Lutz Hein ◽  
Norbert Roewer ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Blood Pressure Lowering Effect ◽  
Α2 Adrenoceptors ◽  
Arterial Blood ◽  
Neuroprotective Function

We assessed the neuroprotective potential of α2-adrenoceptors in ischemic stroke using mice with targeted deletions of individual α2-adrenoceptor subtypes (α 2A−/−, α 2B−/−, α 2C−/−, α 2A/C−/−). The effects of the α2-adrenoceptor agonist clonidine were studied in parallel. Focal cerebral ischemia was induced with or without clonidine pretreatment by transient middle cerebral artery occlusion. Neurologic outcome and infarct volumes were evaluated on day 1. Cerebral blood flow (CBF) and mean arterial pressure were determined. α2- Adrenoceptor null mice did not display larger infarct volumes compared with wild-type (WT) mice under basal conditions ( P>0.05). In line with this finding, pretreatment with clonidine did not protect from ischemic brain damage in WT mice or α 2A−/−, α 2B−/−, and α 2C−/− mice. Clonidine induced smaller infarct volumes only in α 2A/C−/− mice ( P < 0.05), but this did not translate into improved neurologic function ( P > 0.05). Importantly, while clonidine caused a significant decrease in arterial blood pressure in all groups, it had no blood pressure lowering effect in α 2A/C−/− mice, and this correlated with higher CBF and smaller infarct volumes in this group. In summary, we could not demonstrate a neuroprotective function of α2-adrenoceptors in focal cerebral ischemia. Careful controlling of physiological parameters relevant for stroke outcome is recommended in experimental stroke studies.

Animal Models in Psychiatry

2020 ◽  
pp. 167-192
Author(s):  
Richard McCarty
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Learned Helplessness ◽  
Molecular Targets ◽  
Essential Element ◽  
Inbred Strains ◽  
Behavioral Tests ◽  
Single Animal ◽  
Stressful Stimulation ◽  
Helplessness Model

Darwin made a compelling case that studies of animals could provide insights into the behavior of humans. Early studies by Pavlov and Harlow paved the way for further developments of animal models of psychiatric disorders. Seligman and Maier’s learned helplessness model continues to be employed in laboratory studies of stress and depression. It has become clear that no single animal model can possibly reproduce all of the critical facets of a mental disorder in humans. However, animal models do provide an essential element in attempts to understand the mechanisms that underlie mental disorders and to reveal molecular targets for the development of new drug therapies. Concerns have been raised about the reproducibility of laboratory experiments with inbred strains of laboratory mice and rats. Any animal model should be evaluated based upon a battery of behavioral tests and the parameters of stressful stimulation employed in experiments should be chosen with care.

scholarly journals Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice

2019 ◽  
Vol 20 (8) ◽  
pp. 2019 ◽  
Author(s):  
Michael K. Schuhmann ◽  
Peter Kraft ◽  
Michael Bieber ◽  
Alexander M. Kollikowski ◽  
Harald Schulze ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Recombinant Tissue Plasminogen Activator ◽  
Artery Occlusion ◽  
Stroke Outcome ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Stroke Study ◽  
Increased Risk

Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2−/− mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.

scholarly journals Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice

2015 ◽  
Vol 35 (12) ◽  
pp. 2080-2088 ◽  
Author(s):  
Lea Krey ◽  
Fred Lühder ◽  
Kathrin Kusch ◽  
Bozena Czech-Zechmeister ◽  
Birte Könnecke ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Wild Type ◽  
Significant Difference ◽  
Stroke Models

Sirtuin-2 (Sirt2) is a member of the NAD+-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2−/− mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.

scholarly journals Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice

2020 ◽  
Vol 21 (9) ◽  
pp. 3053
Author(s):  
Saurabh Jain ◽  
Eun-Sun Kim ◽  
Donghyun Kim ◽  
David Burrows ◽  
Milena De Felice ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Time Window ◽  
Focal Cerebral Ischemia ◽  
Similar Efficacy ◽  
Human Studies ◽  
Experimental Stroke ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures

l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. We hypothesized that d-carnosine, which is not a substrate for carnosinases, may have a better pharmacological profile and may be more efficacious at lower doses than l-carnosine. To test our hypothesis, we explored the comparative pharmacokinetics and neuroprotective properties of d- and L-carnosine in acute ischaemic stroke in mice. We initially investigated the pharmacokinetics of d- and L-carnosine in serum and brain after intravenous (IV) injection in mice. We then investigated the comparative efficacy of d- and l-carnosine in a mouse model of transient focal cerebral ischemia followed by in vitro testing against excitotoxicity and free radical generation using primary neuronal cultures. The pharmacokinetics of d- and l-carnosine were similar in serum and brain after IV injection in mice. Both d- and l-carnosine exhibited similar efficacy against mouse focal cerebral ischemia. In vitro studies in neurons showed protection against excitotoxicity and the accumulation of free radicals. d- and l-carnosine exhibit similar pharmacokinetics and have similar efficacy against experimental stroke in mice. Since humans have far higher levels of carnosinases, d-carnosine may have more favorable pharmacokinetics in future human studies.

scholarly journals The Protective Role of Immunomodulators on Tissue-Type Plasminogen Activator-Induced Hemorrhagic Transformation in Experimental Stroke: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 11 ◽  
Author(s):  
Yang Ye ◽  
Yu-Tian Zhu ◽  
Hong-Xuan Tong ◽  
Jing-Yan Han
Keyword(s):  
Systematic Review ◽  
Regression Analysis ◽  
Ischemic Stroke ◽  
Animal Models ◽  
Intracerebral Hemorrhage ◽  
Infarct Volume ◽  
Meta Analysis ◽  
Hemorrhagic Transformation ◽  
Experimental Stroke ◽  
The Impact

Background: Recanalization with tissue plasminogen activator (tPA) is the only approved agent available for acute ischemic stroke. But delayed treatment of tPA may lead to lethal intracerebral hemorrhagic transformation (HT). Numerous studies have reported that immunomodulators have good efficacy on tPA-induced HT in ischemic stroke models. The benefits of immunomodulators on tPA-associated HT are not clearly defined. Here, we sought to conduct a systematic review and meta-analysis of preclinical studies to further evaluate the efficacy of immunomodulators.Methods: The PubMed, Web of Science, and Scopus electronic databases were searched for studies. Studies that reported the efficacy of immunomodulators on tPA-induced HT in animal models of stroke were included. Animals were divided into two groups: immunomodulators plus tPA (intervention group) or tPA alone (control group). The primary outcome was intracerebral hemorrhage, and the secondary outcomes included infarct volume and neurobehavioral score. Study quality was assessed by the checklist of CAMARADES. We used standardized mean difference (SMD) to assess the impact of interventions. Regression analysis and subgroup analysis were performed to identify potential sources of heterogeneity and evaluate the impact of the study characteristics. The evidence of publication bias was evaluated using trim and fill method and Egger’s test.Results: We identified 22 studies that met our inclusion criteria involving 516 animals and 42 different comparisons. The median quality checklist score was seven of a possible 10 (interquartile range, 6–8). Immunomodulators improved cerebral hemorrhage (1.31 SMD, 1.09–1.52); infarct volume (1.35 SMD, 0.95–1.76), and neurobehavioral outcome (0.9 SMD, 0.67–1.13) in experimental stroke. Regression analysis and subgroup analysis indicated that control of temperature and time of assessment were important factors that influencing the efficacy of immunomodulators.Conclusion: Our findings suggested that immunomodulators had a favorable effect on tPA-associated intracerebral hemorrhage, cerebral infarction, and neurobehavioral impairments in animal models of ischemic stroke.

scholarly journals A Systematic Review and Meta-Analysis of Erythropoietin in Experimental Stroke

2009 ◽  
Vol 30 (5) ◽  
pp. 961-968 ◽  
Author(s):  
Mikael Jerndal ◽  
Kalle Forsberg ◽  
Emily S Sena ◽  
Malcolm R Macleod ◽  
Victoria E O'Collins ◽  
...  
Keyword(s):  
Systematic Review ◽  
Animal Models ◽  
Infarct Size ◽  
Potential Benefit ◽  
Focal Cerebral Ischemia ◽  
Meta Analysis ◽  
Experimental Stroke ◽  
Inclusion Criteria ◽  
The Impact ◽  
Neurobehavioral Outcome

Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial.

scholarly journals Rich-Club organization: an important determinant of functional outcome after acute ischemic stroke

2019 ◽  
Author(s):  
Markus D. Schirmer ◽  
Sofia Ira Ktena ◽  
Marco J. Nardin ◽  
Kathleen L. Donahue ◽  
Anne-Katrin Giese ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Prediction Models ◽  
Brain Magnetic Resonance Imaging ◽  
Lesion Volume ◽  
Stroke Outcome ◽  
Rich Club ◽  
The Rich ◽  
Magnetic Resonance Imaging Mri

AbstractObjectiveTo determine whether the rich-club organization, essential for information transport in the human connectome, is an important biomarker of functional outcome after acute ischemic stroke (AIS).MethodsConsecutive AIS patients (N=344) with acute brain magnetic resonance imaging (MRI) (<48 hours) were eligible for this study. Each patient underwent a clinical MRI protocol, which included diffusion weighted imaging (DWI). All DWIs were registered to a template on which rich-club regions have been defined. Using manual outlines of stroke lesions, we automatically counted the number of affected rich-club regions and assessed its effect on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS; obtained at 90 days post-stroke) scores through ordinal regression.ResultsOf 344 patients (median age 65, inter-quartile range 54-76 years) with a median DWI lesion volume (DWIv) of 3cc, 64% were male. We established that an increase in number of rich-club regions affected by a stroke increases the odds of poor stroke outcome, measured by NIHSS (OR: 1.77, 95%CI 1.41-2.21) and mRS (OR: 1.38, 95%CI 1.11-1.73). Additionally, we demonstrated that the OR exceeds traditional markers, such as DWIv (ORNIHSS 1.08, 95%CI 1.06-1.11; ORmRs 1.05, 95%CI 1.03-1.07) and age (ORNIHSS 1.03, 95%CI 1.01-1.05; ORmRs 1.05, 95%CI 1.03-1.07).ConclusionIn this proof-of-concept study, the number of rich-club nodes affected by a stroke lesion presents a translational biomarker of stroke outcome, which can be readily assessed using standard clinical AIS imaging protocols and considered in functional outcome prediction models beyond traditional factors.

Inflammational Animal Models for Schizophrenia

2015 ◽  
Vol 223 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Georg Juckel
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Immune Activation ◽  
Microglial Activation ◽  
Treatment Options ◽  
Early Adulthood ◽  
Brain Regions ◽  
Synaptic Connections ◽  
Preventive Interventions ◽  
Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

The Animal Models for Hemorrhage and Thrombosis in the Neonate

1987 ◽  
Vol 57 (01) ◽  
pp. 118-122 ◽  
Author(s):  
C Thomas Kisker
Keyword(s):  
Animal Models ◽  
Normal Development ◽  
Relevant Information ◽  
Relevant Model ◽  
Current Information ◽  
Single Animal ◽  
Hemostatic Disorders ◽  
Thrombotic Diseases

SummaryAnimal models have added significantly to our understanding of adult hemorrhagic and thrombotic diseases. Few models, however, have been developed for studies of the hemostatic disorders in the fetus and newborn. This report reviews the current information on animal models of fetal and neonatal hemostasis. The requirements of a relevant model are addressed and previous studies using fetal and neonatal animal models are reviewed. A recommendation of a single animal for all studies of fetal and neonatal hemostasis is not possible. However, the lamb has been the most frequently studied and appears to provide relevant information regarding normal development and the factors which may adversely influence hemostasis in the fetus and newborn.

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