Rodent stroke models provide the experimental backbone for the in vivo determination of the mechanisms of cell death and neural repair, and for the initial testing of neuroprotective compounds. Less than 10 rodent models of focal stroke are routinely used in experimental study. These vary widely in their ability to model the human disease, and in their application to the study of cell death or neural repair. Many rodent focal stroke models produce large infarcts that more closely resemble malignant and fatal human infarction than the average sized human stroke. This review focuses on the mechanisms of ischemic damage in rat and mouse stroke models, the relative size of stroke generated in each model, and the purpose with which focal stroke models are applied to the study of ischemic cell death and to neural repair after stroke.

https://link.springer.com/content/pdf/10.1602%2Fneurorx.2.3.396.pdf

Rodent models of focal stroke: size, mechanism, and purpose.

Ischemic stroke is a devastating disease with a complex pathophysiology. Animal modeling of ischemic stroke serves as an indispensable tool first to investigate mechanisms of ischemic cerebral injury, secondly to develop novel antiischemic regimens. Most of the stroke models are carried on rodents. Each model has its particular strengths and weaknesses. Mimicking all aspects of human stroke in one animal model is not possible since ischemic stroke is itself a very heterogeneous disorder. Experimental ischemic stroke models contribute to our understanding of the events occurring in ischemic and reperfused brain. Major approaches developed to treat acute ischemic stroke fall into two categories, thrombolysis and neuroprotection. Trials aimed to evaluate effectiveness of recombinant tissue-type plasminogen activator in longer time windows with finer selection of patients based on magnetic resonance imaging tools and trials of novel recanalization methods are ongoing. Despite the failure of most neuroprotective drugs during the last two decades, there are good chances to soon have effective neuroprotectives with the help of improved preclinical testing and clinical trial design. In this article, we focus on various rodent animal models, pathogenic mechanisms, and promising therapeutic approaches of ischemic stroke.

Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia.

The technology used for magnetic resonance (MR) procedures has evolved continuously during the past 20 years, yielding MR systems with stronger static magnetic fields, faster and stronger gradient magnetic fields, and more powerful radiofrequency transmission coils. Most reported cases of MR-related injuries and the few fatalities that have occurred have apparently been the result of failure to follow safety guidelines or of use of inappropriate or outdated information related to the safety aspects of biomedical implants and devices. To prevent accidents in the MR environment, therefore, it is necessary to revise information on biologic effects and safety according to changes that have occurred in MR technology and with regard to current guidelines for biomedical implants and devices. This review provides an overview of and update on MR biologic effects, discusses new or controversial MR safety topics and issues, presents evidence-based guidelines to ensure safety for patients and staff, and describes safety information for various implants and devices that have recently undergone evaluation.

MR procedures: biologic effects, safety, and patient care.

Animal models of neurological deficits are essential for the assessment of new therapeutic options. It has been suggested that rats are not as appropriate as primates for the symptomatic modelling of disease, but a large body of data argues against this view. Comparative analyses of movements in rats and primates show homology of many motor patterns across species. Advances have been made in identifying rat equivalents of akinesia, tremor, postural deficits and dyskinesia, which are relevant to Parkinson's disease. Rat models of hemiplegia, neglect and tactile extinction are useful in assessing the outcome of ischaemic or traumatic brain injury, and in monitoring the effects of therapeutic interventions. Studies in rodents that emphasize careful behavioural analysis should continue to be developed as effective and inexpensive models that complement studies in primates.

Animal models of neurological deficits: how relevant is the rat?

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke Furthermore, this model is characterized by reliable and well-reproducible infarcts Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis However, for many reasons, preclinical stroke research has a low translational success rate One factor might be the choice of stroke model Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models

/pdf/animal-models-of-ischemic-stroke-and-their-application-in-u7m04eip95.pdf

Animal models of ischemic stroke and their application in clinical research.

ENDOTHELIN 1 (ET-1) was unilaterally applied onto the surface of the dorsal frontoparietal cortex of the rat. Cortical blood flow measurements using laser-Doppler flowmetry demonstrated dose-dependent reductions of frontoparietal cortical blood flow. Histological analysis demonstrated dose-related lesions and the time course was followed using MRI. The lesions appear to be associated with a large penumbra area indicated by morphological characteristics. Thus, cortical surface exposure to ET-1 may produce graded lesions of the frontoparietal cortex related to local ischemia.

Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia

High intensity acoustic noise is an undesirable side-effect in magnetic resonance imaging (MRI) that can cause discomfort and hearing loss in patients and may be an impediment in functional MRI (fMRI) studies of the auditory system. Experimental MRI systems with high magnetic field strengths may generate acoustic noise of higher sound pressure levels (SPLs) than conventional 1.0 and 1.5 T clinical systems. We measured the SPL and spectral content of the acoustic noise generated by the Bruker Biospect 47/40 4.7 T experimental MRI system during scanning sequences commonly used in animal testing. Each sequence generated acoustic noise of high SPL, rapid pulse rates, amplitude-modulated pulse envelopes and multi-peaked spectra. The rapid acquisition with enhancement sequence with a 0.25 mm slice thickness generated SPLs of up to 129 dB peak SPL and 130 dB (A). Fourier analysis of the spectral content of the acoustic noise generated by each MRI sequence showed a wide band of acoustic energy with spectral peaks from 0.2-5 kHz. The intense MRI acoustic impulse noise generated by the 4.7 T system may cause masking of stimuli used in fMRI of the auditory cortex, reduce the hearing acuity of experimental animals and present a risk for unprotected human ears.

Hans F. Grahn

Papers

Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia

Analysis of magnetic resonance imaging acoustic noise generated by a 4.7 T experimental system.