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Can Epilepsy Following Brain Injury Be Avoided?

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The brain is surrounded by a liquid known as cerebrospinal fluid (CSF), which is partly made up of proteins from the blood plasma. It has many functions, including mechanical protection of the brain and distribution of hormones (known as neuroendocrine factors); and it also acts as a barrier against infection. The CSF is separated from circulating blood by a structure known as the blood-brain barrier (BBB). This restricts the passage of harmful toxins and bacteria into the brain, but allows molecules such as oxygen and carbon dioxide to pass in and out respectively. The cells that make up the BBB use special transporters to ensure that glucose from the blood can reach the brain effectively.

Any brain injury, whether through trauma, infection, stroke or tumour, can increase a person's chance of developing epilepsy; but seizures may not actually appear until months or years later. This 'waiting time' is called the latent period. Research is ongoing into exactly what causes epilepsy to develop in these circumstances, and whether a treatment administered in the latent period could prevent it.

Scientists from Israel have made an exciting breakthrough, and their results have been published in the Journal of Neuroscience. This is the culmination of fourteen years' work, so it would be helpful to look at the background of the project.

In 1995, Associate Professor Friedman, who is now at Israel's Ben-Gurion University, had a theory that brain injury causes damage to the BBB, which leads to leakage of blood into the brain. This in turn can cause destruction of brain cells and eventual seizure activity.

In order to explore this idea and find out what exactly in the blood is responsible for this epilepsy development, Friedman joined with Daniela Kaufer, who was then a graduate at Hebrew University. Over 12 years their teams systematically sifted through the components of the blood and found that albumin, the main protein present, was the culprit.

In this study, the researchers used albumin to trigger epilepsy in animal brains, and using advanced examination techniques, found that the albumin binds to receptors known as Transforming Growth Factor (TGF)-beta-1 and TGF-beta-2. This binding leads to the activation of many different genes, including some that reduce the inhibition of neurons. The resulting lack of inhibition causes affected neurons to become hyperexcitable and fire uncontrollably, and this can exhaust or even kill them. In order to compensate for the lost neurons, the nerve networks in the brain reorganise themselves, but this can lead to short-circuiting and, potentially, seizures.
Interestingly, the group noticed that albumin initially activates receptors, not on neurons, but on other cells known as astrocytes. Astrocytes, also called glial cells, are a population of "support cells" in the brain that may play an important role in many disease processes.

Daniela Kaufer, who is now an Assistant Professor at the University of California, has been quoted: "The astrocytes really work well as sponges for glutamate and potassium ions, controlling neuronal excitability.
"Signaling in the TGF-beta pathway changes the properties of astrocytes, so you get higher potassium and glutamate in the vicinity of neurons and hyper-excitability, which makes the neurons start firing together, you get synchronous activity developing, and epilepsy follows."

The team achieved the same genetic changes when they injected the actual TGF-beta1 protein into the brain models. However, when they added drugs that block TGF-beta receptor 1 and TGF-beta receptor 2, they found that these changes were prevented.

Based on these findings, Kaufer commented that it would be reasonable to assume that TGF-beta receptor blockers would work to prevent further damage in models of status epilepticus (SE), as this also opens the BBB.
These findings are encouraging, because they provide a new treatment focus for epilepsy. If they can be applied to humans in the future, epilepsy after brain injury could eventually be prevented in many cases, with drug treatment.
Friedman commented "You can have somebody with no epileptic seizures, but the barrier is open for weeks and months after the trauma. We have initial evidence to suggest that these patients are much more susceptible to the development of epilepsy."

Kaufer added "The idea is to identify the brain injury patients that are very susceptible to epilepsy development - which may be possible to achieve using brain imaging - and then treat only those, not everybody, with a pretty benign drug that blocks the growth factors. At least in the rats, that works now."

Friedman and his group in Ben-Gurion's Brain Imaging Research Center, are currently developing new imaging tools that can measure BBB opening in humans with brain injuries. We look forward to hearing about their progress.

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