Stroke Research: The importance of testing medicines in animals at risk of stroke

By Connie Lathe, BSc

A Background to Stroke

One in six people will have a stroke during their life, and every 6 seconds someone in the UK will suffer a bleed (haemorrhagic stroke) or clot (ischaemic stroke) that deprives their brain cells of oxygen. These two types of stroke represent 15% and 85% of all cases respectively and are illustrated in the diagram below.

A reduction in the brain’s oxygen supply can lead to lasting cell damage and even death. As a result, stroke survivors can have a variety of symptoms ranging from mild to severe, primarily depending on the area of the brain affected and the time between stroke onset and treatment. Common post-stroke effects include a weakness in the arms and legs, difficulty with speaking, reading and writing, and problems with memory and organised thought.

There are a number of medicines available for people who have had a stroke. However, the majority of these can only be used in cases where the patient has had a clot (not a bleed) and treatment must be given during a short window following the stroke (no more than 6 hours after onset). Two procedures, thrombolysis (the breakdown of the clot using drugs) and thrombectomies (the physical removal of the clot) are the most effective treatments for an ischaemic stroke; however, they only increase the chances of a better outcome by up to 30% and 50%, respectively.

Researchers are therefore interested in finding alternative ways to treat patients who have had a stroke or are at risk of having a stroke. For example, one line of research in developing new stroke treatments is to investigate the possibility of limiting stroke damage, by treating patients at high-risk of stroke with medicine before a clot or bleed happens.

Who Gets a Stroke?

Before drugs are tested in humans, they are first tested in animals that have a similar disease as the patients that the drug has been designed for. This is to make sure that the drug is safe and works in the desired way.

In humans, strokes do not often occur randomly; there are a number of factors that have been found to increase the risk of stroke. Such risk-factors can be divided into modifiable and non-modifiable; for example, it is possible to reduce alcohol intake (modifiable), but not change your ethnicity (non-modifiable). Some of these are shown in the table below.

In stroke research, this means initiating a clot or bleed in animals that are at an increased risk of having a stroke, however, previous stroke research has often used animals that are young, healthy and active – a demographic in humans that rarely experience a clot or bleed in the brain.

Consequently, it has been noticed that the beneficial results recorded using drugs in these animal models are not easily reproduced when treatment is repeated in human clinical trials.

Therefore, it has been suggested that young, healthy and active animals do not provide a good test setting for stroke treatments, given that they do not accurately represent the patient group who are most likely to have strokes (i.e. people who are old, unhealthy, and inactive).

Given these known risk factors in humans, a suitable animal comparison would exhibit one or more of these risk factors.

Example of An Animal at Risk of Stroke

A type of rat known as the spontaneously hypertensive rat (SHR) is now regularly used in experiments that test stroke medication. This is because starting at roughly four weeks of age, these rats display a gradual rise in blood pressure (BP) until they are between 16 to 28 weeks old, at which point their mean arterial BP will stabilise around 187 mmHg. This is significantly higher than their healthy counterparts, whose BP averages around 101 mmHg, successfully mimicking the rise in BP seen in humans with high blood-pressure.

This type of rat is particularly effective, because high blood-pressure is the biggest modifiable risk-factor in humans.

The University of Glasgow is currently investigating potential stroke treatments in this type of rat, with other institutions choosing to select animals that exhibit alternative stroke risk-factors such as obesity and old-age. In the future, the ideal model will likely incorporate a combination of these risk-factors, as seen in a large percentage of humans who have a stroke.

Animals that exhibit the most common combinations of stroke risk-factors are therefore thought to offer the best chance of aiding the transition of treatments from research to successful human clinical trials.