Naked mole rat treatment for stroke

A stroke occurs every 2 seconds worldwide and is the second largest cause of death. When a stroke happens, the most important tissues of our body, the brain and heart, are starved of oxygen causing cell damage. To improve therapies for stroke patients we need to understand how the human body copes without oxygen and one researcher at the University of Cambridge thinks he may have found the answer in the form of a small rodent called a naked mole rat. Dr Ewan St John Smith and his colleagues were able to identify a new mechanism used by the naked mole rats to maintain an energy supply to the cells in their body without using oxygen. He told Tom Crawford more about these fascinating creatures…

Ewan - Politely, one can describe them as a cocktail sausage with legs and teeth, but they are very unusual rodents. They are about the same size as a mouse and they are very unusual for a number of aspects. They are the only cold blooded mammal we are aware of, they live for over 30 years even though based on their maths you’d predict them to live somewhere between 3 and 5. They also have a very unusual social structure which is what we call eusocial, so that’s when you have a colony of animals up to 300, but usually near a hundred for the mole rats, and it’s led by a queen who’s the only breeding female. There’s a couple of males who are the breeding males and all the other animals are workers so it’s a very highly social mammal.

Tom - You’ve discovered how they are able to survive without oxygen and still produce energy but why is this important?

Ewan - The mole rats live in these large colonies underground, so they are permanently subterranean rodents and, obviously, if you’ve got a lot of animal underground they’re breathing.  If you’re breathing they’re using up the oxygen and you’re generating a lot of carbon dioxide, but there’s not the same supply of fresh air there is for us when we’re just walking around above ground. So these animals have adapted throughout evolution to an environment that’s low in oxygen so it’s important for them to be able to function normally that they can deal with much lower levels of oxygen than we can.

Tom - What did you do specifically in these experiments?

Ewan - In these experiments we first wanted to identify how resistant is the naked mole rat to this lack of oxygen, a condition we call hypoxia. If we compare this first of all to the human condition; when a human has a stroke there's a blood clot usually in the brain which prevents oxygen getting to the brain and the nerve cells - where there is no oxygen - die. What we want to do in stroke is try to protect the nerve cells from dying so that fewer cells die, so it’s all about getting oxygen to the right place.

What we were trying to see in the mole rat was how, considering they evolved in this low oxygen environment, how resistent were they to a lack of oxygen. So when you expose a mouse -a model of our human - to a lower level of oxygen they, like humans, experience brain death quite quickly. Whereas the mole rat is able to go for almost 20 minutes with experiencing no brain death and the animals are perfectly happy and are able to survive this period of complete absence of oxygen.

Tom - Having identified this behaviour i n the mole rate, the question facing Ewan and his colleagues was how are they doing this on a cellular level? In particular, what’s going on with the key organs that are needed to sustain life - the heart and the brain?

Ewan - When the naked mole rat is exposed to this long level of lack of oxygen, the heart rate drops dramatically to about 20/25% of its normal rate, but it keeps going. So somehow, it must be getting energy from somewhere in the absence of oxygen. It can’t generate energy by the normal processes that we, as mammals, do, so the heart keeps on going. Similarly, if we look at the brain, the brain activity is able to keep on going in the absence of oxygen. Obviously not forever, but for a much longer period of time compared to the mouse.

So the question is then: how is the mole rat able to do this; how is that the cells and the heart and the brain can keep on going?  And again, coming back to stroke, this is really exciting. If we can understand how the mole rat cells keep going, maybe this is way for which we can generate new therapies to prevent nerve cells in a human patient dying when they have a stroke.

Tom - As humans, there are different ways that we can generate energy in cells. Some of them require oxygen, which we call aerobic respiration, and some of them don’t and this is anaerobic respiration. An important part of the anaerobic respiration process is called glycolysis and this requires glucose, so sugary syrup. But the mole rats are actually doing glycolysis using something else…

Ewan - What we were able to identify is that the mole rat is able to use fructose to generate energy in the absence of oxygen. Now we can also use fructose, but the difference is in the mole rate in the heart and in the brain, it’s got much higher levels of a protein that enables cells to transport fructose from the blood into the cells. So in this period where there’s a lack of oxygen and it uses up all the normal glucose supplies within cells, the mole rat can utilise fructose in the blood to keep on generating energy. And again, this can’t go on forever, but it’s able to for a much longer period of time, sustain a basal level of activity in the cells so they don’t die.

Tom - So now that we understand how the mole rats do this, is the idea to try and make human brain cells and heart cells do this glycolysis using fructose?

Ewan - I think part of the problem is, obviously, if you have stroke patient we know that we can’t just inject them with a large bolus of fructose because they don’t have the transport proteins to get them into the brain cells, for example. So we’ve got this new way of understanding how the mole rat cells keep going. And I think what it’s really done is open our eyes up understanding more about what is enough, what is sufficient for nerve cells to keep going so they don’t need to be performing aerobic respiration as we usually think. It’s a huge way forward in understanding how the nerve cells, or how the nerve cells can survive without oxygen, and the more we understand about that, the greater chance we have of generating a novel neuroprotective strategy for preventing nerve cell death in humans who’ve had a stroke.