Sealing the leaking brain solves seizures

Descriptions of the brain often focus on the number of brain cells – neurons and the supporting glia cells. The numbers are, of course, immense – 85 billion neurons and a similar number of glia are present inside the human brain. Neurons are information messengers. They use electrical impulses and chemical signals to transmit information between different areas of the brain, and between the brain and the rest of the nervous system. Glia are non-nerve cells, that provide essential support to neurons, including insulation and communication as well as nutrient and waste transport. But glia are not the only neighbours of importance to neurons. Close by every neuron is a small blood vessel called a capillary. Exactly how close you ask? Well about 10 micrometres. When we consider that  a micrometre is a millionth of a meter and the thinnest human hair is about 10 times wider than this it gives us a real sense of this proximity. This blood supply is absolutely essential for the brain to work. The brain is a very energy hungry organ. Neurons are continuously firing electrical signals which  require a lot of energy to generate. Circulating blood delivers the essential energy the brain  needs in the form of sugar which is glucose and the gas which is oxygen.  These react and generate cell power called ATP.

Our  blood also contains all sorts of nasty things  we absolutely do not want getting into our brains. These include breakdown products of food, additives, lactic acid from exercise, high or low levels of sodium and potassium and even the cells of our immune systems. All of these substances can have dramatic effects on our brain cells, often making them go literally haywire. However, help is at hand. A safety net or wall called the Blood Brain Barrier (BBB for short) protects our brains from the dangers of our own blood and most of the unhelpful things circulating in it.  

What is this wall made of? The BBB is made from the joined together cells of the blood vessel wall. These cells, called endothelial cells,  seal together extremely tightly, preventing most things from passing out of the blood into the brain. Luckily, there is a way to get the things that are needed through. Within the walls of these cells we find specialised transporters. These act like a gate. When the gate opens it allows a particular type of molecule to pass through (and very often a second molecule hitches a ride too, a handy way to make the best use of the energy used in the process). A molecule is the smallest piece of any substance that has all of the physical and chemical properties of that substance. The molecules allowed through are those ones we need while those we don’t need can’t come in. Gases such as oxygen and carbon dioxide can pass freely through but other substances including water have a special transport system to let them in.

So what does all this stuff about the Blood Brain Barrier have to do with epilepsy? For several years researchers interested in what causes epilepsy kept finding proteins, which are normally only found in the bloodstream, lurking and surrounding neurons. These proteins appeared to have leaked from the brain capillaries. This leak was worst in the areas of the brain where seizures were generated. They also found that injecting tiny amounts of these blood proteins into the brain of a mouse or puffing some onto brain cells in a dish, caused changes in brain cell firing that in some cases built up into a seizure. This suggested to the researchers that a properly working BBB was important. A leaky BBB would allow substances from the blood to pass into the brain where their effects appeared to be harmful. Secondly, it got the researchers thinking that repairing the BBB might be a new way to treat epilepsy.  Matthew Campbell, a Professor at Trinity College Dublin, was one such researcher. Some years ago, Matthew had found that creating a leaky BBB in mice caused behaviour that looked a bit like a seizure. Now, in a paper recently published in Nature Communications, members of his laboratory and the FutureNeuro, the SFI Research Centre for Chronic and rare Neurological Disorders, have provided important new evidence that having tight, sealed gaps between the cell walls of the capillaries in the brain is critical because when those become leaky it can indeed cause epilepsy.

The researchers first asked whether the BBB was leaky in patients wth epilepsy. New brain scanning techniques mean it is possible to spot where the BBB is leaking. This is done by checking if an injected chemical that normally stays inside the vessels, starts appearing outside those sites in an MRI scan. They found that the BBB was leaky in patients experiencing frequent seizures. This was most obvious at the place in the brain where the seizures were strongest. But they could also see areas of leaky vessels further away suggesting that the BBB may open-up as a seizure spreads around the brain, causing leaks in other places. This was not the first time that this been observed. What was different this time was that the researchers re-scanned the patients after they had surgery to stop their seizures. In patients succesfully treated for epilepsy, the brain scans showed an improvement of the BBB. They had fewer seizures and less BBB leaks.

The research team next asked why is the BBB leaky and later asked if there is anything that can be done to stop this? They discovered a problem with the “glue” holding the cell walls together; this glue is made from a protein claudin-5. Claudin -5 is considered one of the most important proteins for the BBB to work. The researchers estimated that a single brain capillary cell contains 18 million claudin-5 molecules! When the researchers measured the amount of claudin-5 in the blood vessels from patients with epilepsy, they found levels were well below what they should be. Also, under a microscope they could see that, rather than forming a long continuous line along the edge of the blood vessels, there were regular gaps between cells where claudin-5 should have been present. Since claudin-5 was needed to hold together the cell walls of the BBB, the loss of claudin-5 could explain why the blood vessels were leaky. However, the evidence was not entirely conclusive. Perhaps having epilepsy caused a change in the production of the protein? What came first? Was a loss of claudin-5 alone sufficient to cause epilepsy?

The research team set out to answer the next question. This couldn’t be done using patients and so they turned to mice which have a very similar BBB and can also develop epilepsy under various conditions. The blood vessels inside the brains of mice that developed epilepsy had the same pattern of changes to claudin-5. They next made a change to the DNA of a normal mouse that allowed them to switch claudin-5 on or off. Within a few weeks of switching off claudin-5 levels in the brain, the BBB became leaky and mice began to have seizures. This was confirmed by recording electrical activity from the brain using a system  similar to an EEG machine that is used to diagnose epilepsy. Mice lacking one copy of the claudin-5 gene were also sensitive to developing epilepsy. These experiments provided direct proof that making the barrier leaky is enough to cause epilepsy.

Next, the researchers allowed levels of claudin-5 to go back to normal. The seizures stopped. This was further proof that BBB leakage alone can cause epilepsy but it also revealed that the process was reversible. If it was reversible in mice then perhaps the same would be true in people.

Could restoring the BBB help repair the BBB in humans and stop seizures? We don’t know. This is, however, a very exciting area of research which promises to drive the development of new therapies aimed at the BBB for epilepsy. What kind of therapy might work this way? To begin to answer this the team turned to a drug that previously had been shown to increase claudin-5 levels. By injecting this into mice with a leaky BBB they were able to reduce seizures. This drug or indeed one like it or perhaps using  gene therapy to deliver the claudin-5 gene can be explored in the future.

The study is important because it shows us again that epilepsy can arise from many different causes.  It also shows us that the correct functioning of the blood vessels that supply brain cells is critical. We now have a new target to go after. What are some of the next questions? How leaky does the barrier have to be for epilepy to occur? What are the molecules that pass through the barrier that pose the problem? Is closing the barrier always effective or is there a period of time after which closing it is no longer effective? Why do seizures open the BBB? What is causing the level of claudin-5 to drop? Answers to these questions and the next steps towards a therapy mean exciting times ahead for improving the lives of patients with epilepsy and their families!

Green et al. Microvascular stabilization via blood brain barrier regulation prevents seizure activity. Nature Communications 13, 2003 (2022)


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