Proteins in the brain protect against cerebral malaria

April 19, 2013 - 06:14
Article from University of Oslo

Proteins in the brain called water channels are shown to be important for surviving malaria. This may lead to entirely new medicines for a disease which takes hundreds of thousands of lives every year.

Cerebral malaria occurs when the malaria parasite P. falciparum attacks the brain. The parasite is transmitted via the malarial mosquito and infects the red blood cells. (Photo: Colourbox)

Researchers at the University of Oslo, in collaboration with US researchers, have demonstrated that the water channel proteins in the brain protect against cerebral malaria.

The results have been published in American journal Proceedings of the National Academy of Sciences (PNAS).

"This finding can help us to understand why we actually have these water channels. The water channels provide a greater chance of surviving cerebral malaria, and presumably also other infectious diseases of the brain", says one of the researchers behind the study, Professor of Anatomy Mahmood Amiry-Moghaddam.

"The knowledge this gives us may in the long term lead to the development of new treatment methods, for example by finding a treatment that stimulates the action of the water channels", he says.

Cerebral malaria occurs when the malaria parasite P. falciparum attacks the brain.

The parasite is transmitted via the malarial mosquito and infects the red blood cells. The disease is widespread in tropical and sub-tropical regions of Africa, Asia, the Middle East, Latin America and Oceania. It particularly affects children under the age of ten, and is the cause of a significant proportion of worldwide child mortality.

A beneficial role after all

Researchers throughout the world have long scratched their heads over why the brain has so many water channels.

A water channel is a protein – known by researchers as aquaporin – that exists naturally in the human body. Aquaporin-4 is the most frequently occurring water channel in the brain, and until now it has been known to have a harmful rather than a useful function.

Research has shown that aquaporin-4 exacerbates the effect of stroke or other conditions that cause swelling of the brain – so-called cerebral oedema. In diseases of this type the water channels contribute to an increase in the fluid accumulation in the brain, which may result in dangerous pressure.

Only during the last few years has research begun to reveal beneficial effects of water channels. In 2011 Amiry-Moghaddam’s group demonstrated that water channels are important for cell volume regulation. Cell volume regulation is an important mechanism to enable cells to avoid large changes in volume, for example swelling or contraction.

This mechanism is very important for cell survival. Last year a study was published by Erlend Nagelhus et al. which showed that water channels may be involved in removing waste products from the brain. The new study thus joins one of several studies documenting beneficial effects of water channels, but it also presents something completely new:

"Our new study is the first in which a direct link can be seen between having water channels and an increased chance of surviving a disease", says Amiry-Moghaddam.

Water channels removed in mice
Mahmood Amiry-Moghaddam. (Photo: Gunnar F. Lothe, UiO)

Amiry-Moghaddam and colleagues studied the course of cerebral malaria in mice with water channels intact and mice which have had these removed, respectively. They found that the mice without water channels became seriously ill a day before those that had water channels. The mice without water channels showed a much higher degree of disease-related behaviour, and the disease had a fatal outcome for them 24 hours earlier than for the normal mice.

Five days after the infection occurred, the researchers began treating both groups of mice with the malaria drug chloroquine. In that case 80 per cent of the normal mice survived, compared to just 20 per cent of the mice that lacked water channels.

"This difference is dramatic", says Amiry-Moghaddam.

"Both with and without treatment, we can clearly see that water channels provide a survival advantage. We do not yet know what mechanism lies behind this, but we have a number of theories."

Refutes earlier studies

Few groups of researchers have previously worked with malaria and water channels, and earlier studies have actually reached the opposite conclusion to that of Amiry-Moghaddam and colleagues. Since cerebral malaria leads to swelling of the brain, aquaporin blockers have been proposed as a potential treatment method.

However, these studies have been less thorough than the one which Amiry-Moghaddam and colleagues have now conducted.

"We have used all available methods", says Amiry-Moghaddam.

"We have looked at everything from behaviour to molecular biology and different microscopy techniques, for example electron microscopy. Our results will doubtless attract some attention, not least because they are thoroughly substantiated."

Need for other drugs?

Up until today researchers have worked on developing drugs that block the effect of water channels. These types of drugs will be able to provide effective early treatment of strokes and cerebral oedema.

Given the new findings on cerebral malaria, researchers may perhaps also begin to develop water channel activators, which strengthen the effect of water channels, but this is still some way off.

"At present neither aquaporin blockers nor activators exist. However, we have several ongoing projects which are addressing the regulation of aquaporin-4 in the brain. The first stage is to prove that aquaporin-4 can be regulated. After that we will look at how we can develop this into new forms of treatment", says Amiry-Moghaddam.

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