Developing drugs to reduce brain impairment after stroke

March 17, 2014 by Frederic Meunier, The Conversation
An emerging drug treatment is effective in mice but translating these results to humans will take time. Credit: TheTun/Shutterstock

Stroke claims five million lives worldwide each year and is the second biggest killer after ischaemic heart disease. Of those who survive, a significant number (around five million) live with neurological deficits that profoundly affect their quality of life.

Current treatment for ischaemic , which results from a blood clot, aren't very effective. But research published by my colleagues and I today in the journal Nature Communications shows an emerging drug treatment is effective in mice and could one day reduce the neurological impact in people who've suffered an ischaemic stroke.

By 2020, the World Health Organization predicts that worldwide, the number of years lost to disability resulting from stroke will reach 61 million. The economic burden is similarly massive, costing Australia $49.3 billion a year. So finding better treatments is crucial.

Brain inflammation after stroke

Quick treatment is one way to enhance the prospect of recovering from a stroke.

If patients are treated within around three hours of the stroke, the stroke-inducing clots can be broken down relatively efficiently using a substance called tissue plasminogen activator (tPA). This allows the blood to start flowing again, supplying the brain with the oxygen required to keep the tissue alive.

But after the clot is removed and blood starts flowing, the body produces an unwanted neuroimmune response. This occurs because the damaged brain tissue contains elevated levels of molecules known as proinflammatory cytokines, which regulate the body's response to infection, inflammation and trauma.

These cytokines are able to recruit many other immune cells to the area, leading to further .

Limiting the initial release of these cytokines should therefore help to decrease the excessive local inflammatory response, leading to a decrease in tissue damage and better patient outcomes.

Targeting a critical molecule

Ischaemic strokes are caused by blood clots which deprive the brain of blood. Credit: ConstructionDealMkting/Flickr, CC BY

A key cytokine involved in this process is tumour necrosis factor-α (TNF-α). In previous work, we showed that the secretion of TNF-α is dependent on a molecule named phosphoinositide 3-kinase delta (PI3Kδ). For our latest study, we hypothesised that PI3Kδ could be similarly involved in stroke.

In collaboration with Garrie Arumugam from the University of Queensland, researchers at Monash University and international colleagues in London and Hamburg, we induced strokes in mice to demonstrate that – as expected – PI3Kδ controlled the release of TNF-α from of the central nervous system.

This suggested to us that by inhibiting PI3Kδ activity, we would be able to prevent the rise in TNF-α secretion and therefore limit inflammation of the brain and cell death.

Two separate lines of evidence indicated this was the case: mice genetically modified to have inhibited PI3Kδ activity had only limited TNF-α release, and mice that were given the PI3Kδ-inhibiting drug CAL-101 showed similar effects.

Further, blocking PI3Kδ activity (through genetic manipulation or medication) decreased blood clot-induced brain damage and resulted in improved performance on neurological tests.

These results indicate that we successfully identified a pathway critical to post-treatment inflammation of the brain, and that we could limit the damage by blocking PI3Kδ, a key molecule within that pathway.

While the played a role in identifying the signalling pathway involved, it is the efficacy of CAL-101 that is particularly exciting and relevant to stroke therapy. Not only was the drug effective in improving post-stroke recovery, but its effects could be seen when given up to three hours after the clot was removed and blood started flowing.

Since initial is typically initiated by medically trained staff, CAL-101 (or a related molecule) could potentially be injected alongside tPA to reduce inflammation of the brain and improve .

Taking it to the clinic

Neurological deficits after a stroke profoundly affect the sufferer’s quality of life. Credit: ChameleonsEye/Shutterstock

The next obvious question is whether CAL-101 or a similar derivative may ultimately be used to improve stroke treatment in humans.

Our study was conducted in mice, and translating findings in animal models to the development of clinical therapies can be very difficult – clinical trials of drugs fail frequently due to safety or efficacy concerns.

In positive news, however, CAL-101 (also known as GS-1101 or idelalisib) has recently undergone phase three clinical trials in the United States for the treatment of certain forms of lymphoma and the results look promising.

CAL-101 is therefore a very promising molecule. Not only does it treat lymphomas, it has the potential to alleviate the complications that arise following initial stroke treatment. We're now also looking into other medical conditions that could be improved by reducing of the brain with CAL-101 or a similar compound.

Explore further: Substance naturally found in humans is effective in fighting brain damage from stroke

Related Stories

Substance naturally found in humans is effective in fighting brain damage from stroke

March 11, 2014
A molecular substance that occurs naturally in humans and rats was found to "substantially reduce" brain damage after an acute stroke and contribute to a better recovery, according to a newly released animal study by researchers ...

Halting immune response could save brain cells after stroke

March 13, 2014
A new study in animals shows that using a compound to block the body's immune response greatly reduces disability after a stroke.

Clot busters limit stroke damage despite age; stroke severity

February 13, 2014
Regardless of a patient's age, or severity of stroke, prompt treatment with a clot-busting drug limited stroke-related disability, according to late-breaking science presented at the American Stroke Association's International ...

Stroke survivors may lose month of healthy life for 15-minute delay in treatment

March 13, 2014
Every 15-minute delay in delivering a clot-busting drug after stroke robs survivors of about a month of disability-free life, according to a new study in the American Heart Association journal Stroke.

Peritoneal dialysis as an intervention for stroke patients

September 3, 2013
Ischemic stroke is characterized by an interruption of the blood supply to the brain, which can lead to brain damage and even death. Excess amounts of the excitatory neurotransmitter glutamate are released during stroke events ...

Hands-free ultrasound device with clot-busting drug safe for stroke patients

October 24, 2013
A hands-free ultrasound device combined with a clot-busting drug was safe for ischemic stroke patients in a phase II pilot study, reported in the American Heart Association journal Stroke.

Recommended for you

Could aggressive blood pressure treatments lead to kidney damage?

July 18, 2017
Aggressive combination treatments for high blood pressure that are intended to protect the kidneys may actually be damaging the organs, new research from the University of Virginia School of Medicine suggests.

Quantifying effectiveness of treatment for irregular heartbeat

July 17, 2017
In a small proof-of-concept study, researchers at Johns Hopkins report a complex mathematical method to measure electrical communications within the heart can successfully predict the effectiveness of catheter ablation, the ...

Concerns over side effects of statins stopping stroke survivors taking medication

July 17, 2017
Negative media coverage of the side effects associated with taking statins, and patients' own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially ...

Study discovers anticoagulant drugs are being prescribed against safety advice

July 17, 2017
A study by researchers at the University of Birmingham has shown that GPs are prescribing anticoagulants to patients with an irregular heartbeat against official safety advice.

Protein may protect against heart attack

July 14, 2017
DDK3 could be used as a new therapy to stop the build-up of fatty material inside the arteries

Heart study finds faulty link between biomarkers and clinical outcomes

July 14, 2017
Surrogate endpoints (biomarkers), which are routinely used in clinical research to test new drugs, should not be trusted as the ultimate measure to approve new health interventions in cardiovascular medicine, according to ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.