Animal model of stroke

The historical understanding of stroke began with symptom-based observations, such as paralysis and convulsions, described by Hippocrates as apoplexy. Early treatments like bloodletting targeted symptoms without addressing underlying causes. As knowledge advanced, scholars like Thomas Willis and Jakob Wepfer began identifying the pathophysiological changes behind stroke, laying the foundation for modern medical interventions.^[1]

An animal model of Ischemia and stroke, the image represents the different procedures during a surgical model of an experimental test.

Building on this evolution, animal models of stroke have become essential tools in current research. These models replicate the pathophysiological states seen in human stroke such as blocked blood flow or brain ischemia in animals, including rodents and non-human primates.^[2] Their purpose aligns with the modern shift toward understanding disease mechanisms and improving diagnosis, classification, treatment, and prevention of stroke. In essence, the move from treating symptoms to studying causes in history mirrors today’s use of animal models to explore stroke mechanisms and therapies, continuing the progression from observation to intervention.^[1]

Classification by cause

The term stroke subsumes cerebrovascular disorders of different etiologies, featuring diverse pathophysiological processes. Thus, for each stroke etiology one or more animal models have been developed:

• Animal models of ischemic stroke: where it causes severe brain damage due to sudden loss of blood flow, which creates an infarct core surrounded by the penumbra salvageable tissue, which is then targeted by neuroprotective treatments. To enhance therapy development, better preclinical models were needed, which included older animals and those with related health problems like hypertension, diabetes, obesity, and hyperlipidemia. Aged and comorbid animal conditions are great for developing human treatments for better health.^[3]
• Animal models of intracerebral hemorrhage(ICH): is a severe and non-traumatic type of stroke that affects ~2 million people around the world each year. This illness is the most serious type of stroke and still the least treatable case of study. The sickness causes bleeding in the brain tissue, and it can extend to the ventricles of the brain, where an inflammatory and cell death response is triggered. These responses activate enzymes that release cytokines, leukocytes start migrating, and the breakdown and repair of tissues occur.^[4]
• Animal models of subarachnoid hemorrhage and cerebral vasospasm(SAH): Prior research on SAH and cerebral vasospasm used mechanical, histological, and pharmacological approaches in larger animals (dogs, cats, monkeys). This clinical trial investigates whether rats are a suitable and cost-effective model for the research, which focuses on methods like resolution times, inductions, and vasospasm. The mortality rate for the test subjects was 26%, due to respiratory problems during the first 48 hours of the surgery. The survivors recovered without issues during a three-days period of time. The SAH induction methods mimic natural aneurysmal rupture; SAH is an experimental precision because it can be controlled and analyzed.^[5]
• Animal models of sinus vein thrombosis: Cerebral venous sinus thrombosis (CVST) is a rare type of venous thromboembolism (VTE) that predominantly affects young adults. The risk factors affecting CVST include VTE, infections, tumors, or cranial traumas. This illness can cause thrombosis, edema, ischemia, and hemorrhages located in the tissue of the brain. Due to the array of causes, diagnosis can be difficult to determine, due to limited understanding of CVST pathophysiology and treatment options, animal models are essential for research.^[6]

Transferability of animal results to human stroke

Although multiple therapies have proven to be effective in animals, only very few have done so in human patients. Reasons for this are (Dirnagl 1999):

• Side effects: Many highly potent neuroprotective drugs display side effects which inhibit the application of effective doses in patients (e.g. MK-801)
• Delay: Whereas in animal studies the time of incidence onset is known and therapy can be started early, patients often present with delay and unclear time of symptom onset
• “Age and associated illnesses: Most experimental studies are conducted on healthy, young animals under rigorously controlled laboratory conditions. However, the typical stroke patient is elderly with numerous risk factors and complicating diseases (for example, diabetes, hypertension and heart diseases)” (Dirnagl 1999)
• Morphological and functional differences between the brain of humans and animals: Although the basic mechanisms of stroke are identical between humans and other mammals, there are differences.
• Evaluation of efficacy: In animals, treatment effects are mostly measured as a reduction of lesion volume, whereas in human studies functional evaluation (which reflects the severity of disabilities) is commonly used. Thus, therapies might reduce the size of the cerebral lesion (found in animals), but not the functional impairment when tested in patients.

Ethical considerations

Stroke models are carried out on animals which inevitably suffer during the procedure. These encumbrances are e.g. social stress during single or multiple animal caging (depending on the species), transport, animal handling, food deprivation, pain after surgical procedures, neurological disabilities etc. Thus, according to general consensus, these experiments require ethical justification. The following arguments can be produced to give reason for the conduction of animal experiments in stroke research:

• Stroke is very frequent in humans.
• Stroke is the third leading cause of death in the developed countries.
• Stroke is the leading cause of permanent disability in the developed countries.
• Yet there is no effective treatment available for the majority of stroke patients.
• Currently there are no in vitro methods that could satisfactorily simulate the complex interplay of vasculature, brain tissue, and blood during stroke, and thus could replace the greater part of animal experiments.

During animal experimentation the following prerequisites have to be fulfilled to maintain the ethical justification (“the three Rs”):

• Reduction: Animal numbers have to be kept as little as possible (but as high as necessary - to avoid underpowered studies -) to draw scientific conclusions.
• Refinement: Experiments have to be best planned and to be conducted by trained personnel to minimize the suffering of animals on the one hand and to gain as much knowledge as possible out of the utilized animals.
• Replacement: Whenever possible animal experiments have to be replaced by other methods (e.g. cell culture, computed simulations etc.).