Fruit chemical may prevent organ damage

Behind the Headlines

Thursday November 6 2014

Organ damage can occur at the molecular level

The study looked at the effects of malonate on cell damage

"Could fruit help heart attack patients? Injection of chemical helps reduce damage to vital organs and boosts survival," reports the Daily Mail – "at least in rodents," it should have added.

When tissues are suddenly deprived of oxygen-rich blood (ischaemia), which can occur during a heart attack or stroke, they can suffer significant damage. Further damage can occur once blood supply is restored. Until now, scientists did not know the exact cause of this damage.

Through a set of animal experiments, researchers may have now identified the cause. It could be the result of an increase in a chemical called succinate. Succinate appears to interact with the returning oxygen molecules, creating harmful molecules (reactive oxygen species) that can damage individual cells.

The researchers were able to reduce the amount of succinate produced during periods of mouse heart ischaemia and brain ischaemia by injecting a chemical called dimethyl malonate, which is found in some fruits. This in turn reduced the amount of tissue damage that occurred when the blood supply was returned to the heart and brain.

Although the potential uses are wide ranging, including the use of dimethyl malonate as a potential preventative treatment during heart attacks, stroke or surgery, it will need to be shown to be both effective and safe through human trials.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, St Thomas' Hospital, University College London, the University of Glasgow, and the University of Rochester Medical Centre, New York.

It was funded by the Medical Research Council, the Canadian Institutes of Health Research, the Gates Cambridge Trust, and the British Heart Foundation.

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

The study was accurately reported by the Daily Mail, although the headline was misleading – dimethyl malonate has not yet been used to improve survival in humans. It has only been used in experiments involving mice and rats.

Also, although dimethyl malonate is found in some fruit, the chemical itself has been used, rather than the mice and rats being treated with pieces of fruit.

 

What kind of research was this?

This was an animal study looking at the mechanism behind the injury that occurs to tissues when blood supply is returned after a period of ischaemia (no blood supply).

It was previously believed that tissue injury in these cases, particularly seen after a heart attack, was a non-specific response to the cells regaining oxygen.

The researchers wanted to test the hypothesis that a specific metabolic process causes the injury. And, if so, they wanted to see whether they could develop a drug to limit the process and thereby prevent the injury.

 

What did the research involve?

The researchers looked at chemicals produced in mouse kidneys, livers and hearts, and rat brains after the animal had suffered from ischaemia and had then been reperfused (had their blood and oxygen supply returned).

After identifying one chemical, called succinate, which was increased in all of the tissues studied, the researchers performed a variety of experiments on mouse hearts to investigate the metabolic pathways responsible for the increased level and tissue damage.

They then tested a chemical, dimethyl malonate, that prevented the accumulation of succinate in mouse hearts and rat brains during ischaemia to mimic a stroke.

 

What were the basic results?

The chemical succinate was increased in all of the animal tissues by 3 to 19 times normal levels, and the level of succinate increased with longer periods of ischaemia. It returned to normal levels by five minutes after reperfusion.

Infusing mice with the chemical dimethyl malonate, which can act as an inhibitor of one of the enzymes that can make succinate, significantly reduced the succinate accumulation in the ischaemic heart.

It also stopped the accumulation of succinate in rats' brains during ischaemia (similar to a stroke), and reduced the amount of tissue damage and neurological disabilities.

Succinate is a chemical present in what is known as the citric acid cycle. This cycle is the series of chemical reactions used by all aerobic (oxygen using) organisms to produce energy from fats, carbohydrates and proteins. Interestingly, none of the other chemicals in this pathway were increased during the ischaemia.

Dimethyl malonate is a naturally occurring substance and has been detected in a number of fruits, such as pineapples, bananas and blackberries. It is also widely used in pharmaceuticals, agrochemicals, vitamins, fragrances and dyes.

 

How did the researchers interpret the results?

The researchers concluded they have shown how the chemical succinate accumulates during ischaemia, and that this drives the tissue injury seen when blood supply is returned in a range of rat and mouse tissues.

They found they can reduce the amount of accumulation and damage by using an infusion (injection of a solution) of dimethyl malonate. This research will now pave the way for human trials.

 

Conclusion

This exciting set of experiments has identified the metabolic driver of tissue injury seen when blood supply is returned after a period of ischaemia. The researchers have also shown this process can be limited by using an injection of dimethyl malonate in mice and rats.

It is likely the same increased metabolic processes occur in humans, so there are wide implications for the future, including the potential use of dimethyl malonate injections to prevent tissue damage during surgery.

At present it is unclear how this could be used practically during a heart attack or stroke, and this will be one of many issues that will be explored when human trials are initiated, along with the safety of this treatment.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Could FRUIT help heart attack patients? Injection of chemical helps reduce damage to vital organs and boosts survival. Daily Mail, November 5 2014

Links to the science

Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. Published online November 5 2014

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