Light shed on how brain's stroke defences work

Behind the Headlines

Monday February 25 2013

Stroke is a leading cause of disability in England

Researchers have identified how part of the brain can "shield itself from the destructive damage caused by a stroke," reports BBC News.

These fascinating findings from research in rats could be an early step on the road to discovering new stroke treatments. The study looked at why some types of brain cell are more resistant than others to a lack of oxygen, which can occur during a stroke.

Researchers found that these more resistant cells produced higher levels of the protein hamartin than other nerve cells when they were temporarily starved of oxygen.

By suppressing the production of this protein, researchers found the cells became more vulnerable to dying from oxygen starvation, both in the lab and in living rats. They also found that nerve cells engineered to produce more hamartin became more resistant to temporary oxygen and sugar starvation in the lab.

Reproducing the protein's protective influence might help scientists discover new ways of preventing or treating stroke. However, a great deal more early-stage research in animals is needed before human trials could begin.

 

Where did the story come from?

The study was carried out by researchers from the University of Oxford and other research centres in the UK, Canada, Germany and Greece. It was funded by a UK Medical Research Council grant and the Dunhill Medical Trust.

The study was published in the peer-reviewed journal, Nature Medicine.

BBC News cover this research appropriately and include a balanced quote from Dr Clare Walton, a spokesperson for the Stroke Association: "The findings of this research are exciting, but we are still a long way off from developing a new stroke treatment."

 

What kind of research was this?

This was laboratory and animal research that aimed to find out why some nerve cells in the brain are more resistant to a lack of oxygen than others.

If blood flow to part of the brain is cut off – as happens in ischaemic-type strokes, where a blood clot blocks the flow of blood to the brain – the affected neurons die, as they lack oxygen. Even if treated promptly, this lack of oxygen can lead to brain damage and long-term disability.

However, nerve cells in one area of the brain – the CA3 cells in the hippocampus – have been shown to be resistant to a temporary loss of oxygen caused by a heart attack or open heart surgery, where blood flow is temporarily stopped completely.

It was not known why this happened, but researchers hoped that if they could identify how the cells protect themselves, they may be able to use this knowledge to develop ways of protecting other nerve cells in people who have had strokes.

 

What did the research involve?

In this study, the researchers caused a temporary blockage of blood flow to the front part of the rats' brains to create an approximation of a stroke-like event. They then assessed which proteins were present in the CA3 'resistant' cells and the nearby CA1 nerve cells, which are not resistant. They wanted to see if the CA3 cells produced special proteins not found in CA1 cells that might protect them from damage.

The researchers examined what happened if they blocked the production of the proteins in the laboratory, and then temporarily starved the cells of oxygen and glucose.

They also looked at the effects of genetically engineering rat hippocampal nerve cells in the laboratory to produce high levels of potentially protective proteins. They were particularly interested in whether these engineered cells would protect the brain from the effects of temporary oxygen and glucose starvation.

To confirm their laboratory results, they looked at the effects of suppressing the production of these proteins in the CA3 cells of the hippocampus of live rats, and then induced a temporary stroke-like event.

Researchers also looked at whether suppressing the production of the proteins affected the function of the rat hippocampus. Hippocampal nerve cells are involved in collecting and retaining spatial information, so the researchers carried out what is called an 'open field test' so that they could test the rats' spatial memory.

Open field testing involves putting a rat in an open space and seeing how far they move around and rear up to investigate their surroundings on repeated tests. Normal rats will explore less on repeated tests, as they get used to the space. Rats remember less about their surroundings after a stroke-like event, so move around more on repeated testing than they normally would.

Finally, the researchers carried out various experiments in the lab to look at how the proteins might protect nerve cells.

 

What were the basic results?

The researchers found a number of proteins that CA3 nerve cells produced in response to a 'stroke' at higher levels than CA1 nerve cells.

Of particular interest was the protein hamartin. Its levels increased in the CA3 nerve cells after blood flow was cut off for 10 minutes, with levels remaining high until 24 hours after blood flow was restored.

The researchers found that blocking the production of hamartin in lab-grown nerve cells caused more cells to die after oxygen and glucose starvation (mimicking what would happen in a stroke) than if they had a 'sham' control treatment.

Similar results were found when they repeated the experiment using live rats: in rats who were subjected to a stroke-like event, suppressing hamartin production led to more cell death than in the untreated rats.

The hamartin-suppressed rats did not perform as well on the open field test when compared with the other rat groups (rats that had not been subjected to a stroke-like event, and rats with normal hamartin production who had a stroke-like event).

The researchers also found that more of the nerve cells genetically engineered to produce high levels of hamartin survived if they were temporarily starved of oxygen and glucose.

A series of additional laboratory experiments led the researchers to conclude that hamartin might protect nerve cells by causing the cell to break down its damaged parts and proteins.

 

How did the researchers interpret the results?

The researchers conclude that hamartin appears to provide nerve cells with resistance against temporary loss of oxygen and glucose supply. They say that their findings may help to develop new ways of treating stroke.

 

Conclusion

This research has identified a potential role the protein hamartin plays in protecting nerve cells from death if they are temporarily starved of oxygen and glucose. Animal research such as this is essential for furthering our understanding of how the body and its cells work.

Although there are obviously differences between rats and humans, there are also a lot of biological similarities. This type of research is a good starting point for better understanding human biology.

Treating stroke is very difficult, so new treatments that could prevent nerve cell death would be very valuable. At this stage, the protein hamartin has been identified as a candidate for further investigation.

More studies are needed to identify ways to mimic or increase hamartin production in living animals after a stroke-like event, and to look at the effects of this.

If these studies prove successful, human tests would be needed to make sure any new treatment is effective and safe enough for wider use.

 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Brain's 'stroke shielding' cracked. BBC News, February 24 2013

Links to the science

Papadakis M, Hadley G, Xilouri M, et al. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nature Medicine. Published online February 24 2013

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Stroke: an animation

This animation explains how a stroke happens, the different types of stroke and how lifestyle changes may help to reduce the risks.

Media last reviewed: 03/05/2016

Next review due: 03/05/2018

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