Epilepsy is the common name for a group of neurological diseases. Their common feature is the occurrence of epileptic seizures related to the excessive activity of nerve cells in the brain. The causes of epilepsy vary. Epilepsy that affects children usually has genetic background. However, the disease may also appear in adulthood, as a result of brain damage.

'Epilepsy develops in a few to 20 percent of people after a stroke or injury', says Professor Leszek Kaczmarek, head of the Center of Excellence for Neural Plasticity and Brain Disorders BRAINCITY at the Nencki Institute, winner of the 2000 Foundation for Polish Science Prize.

So far, there have been no drugs to prevent the development of this disease, only drugs that help control epileptic seizures are used.

Meanwhile, the Polish scientist and his team proposed how to pharmacologically stop the process leading to epilepsy in case of brain damage. A study on mice showed that to achieve this, a drug that temporarily inhibits the MMP-9 protein should be administered within a few hours after an injury or stroke.

MMP-9 is an enzyme associated with the work of neurons, which is rapidly released in the brain during an injury and after a stroke. The release of this protein in the brain can initiate a cascade of events that lead to the development of epilepsy.

MEDICINES FOR OTHER DISEASES

Fortunately, research on MMP-9 inhibition does not have to start from scratch. Several substances with this effect have already been tested on patients. For example, MMP-9 inhibitors (blocking substances) have been used in acne preparations. Clinical trials are also underway of a compound with this on children with fragile X syndrome (Kaczmarek is also involved). Another MMP-9 inhibitor has been used in anti-cancer therapy - because cancers use this protein in their expansion.

'In our research, conducted especially by Dr. Barbara Pijet-Binkiewicz, we analysed the effects of several known MMP-9 inhibitors and showed that one of them was capable of penetrating the blood-brain barrier', Kaczmarek explains. This is great news when it comes to preventing the development of epilepsy. Such a drug - administered orally - would therefore allow to prevent the havoc wreaked in the brain by the excess release of MMP-9 as a result of a stroke or injury.

Professor Leszek Kaczmarek adds that the drug with the best prognosis has already been tested on humans - as an anti-cancer agent. 'The study was abandoned because long-term use of this drug (necessary in the fight against cancer) caused pain in patients', he says. However, he points out, the solution proposed by his team only requires a short-term use, for example, a single administration of this compound. With such a dosage, these problematic side effects do not occur.

He adds that a private company (Pikralida) is interested in the commercialisation of this solution and has already obtained funding from the National Centre for Research and Development for further research on this therapy.

MMP-9 RESEARCH

How did the team make this discovery? In the late 1990s, Kaczmarek's team managed to identify the MMP-9 protein in the brain. This enzyme is very important in the learning process and in the development of epilepsy. Since then, the scientist has conducted research that has allowed to better understand why MMP-9 is needed in the brain and how it affects the work of neurons.

'The human brain works like a huge network. It consists of about 85 billion neurons, and each of them can be connected to thousands of others through synapses. That is how neurons communicate with each other', the scientist says.

The signal is transmitted within the neuron by electrical means. However, in order to get to another cell, a chemical pathway is needed. One neuron secretes a neurotransmitter, which reaches another neuron through a synapse and is received by a receptor - a neurotransmitter that captures the protein. When the protein connects with a neurotransmitter, it changes its configuration and function, and transmits the signal further, to the inside of the nerve cell.

Depending on the effectiveness of synaptic transmission, the signal travels through the brain in different ways. 'I use the analogy of a railway network. Tracks allow you to reach various places all over the country. If we want to get from one city to another, you need switches that will transfer the train from one track to another. Synapses play the role of such switches', Kaczmarek compares. He adds that the memory trace is the path that the signal travels in the brain. Memorization and learning have to do with working out repetitive pathways in the signal's journey through the brain.

The MMP-9 protease studied by the Polish team comes out of the postsynaptic part and is responsible for making the postsynaptic part bigger, with more receptors. Thanks to MMP-9, a synapse becomes more passable, and the signal flows more easily along a given pathway. When the signal follows through the same pathway, it is a sign that the individual has learnt something.

'In our previous studies, we have shown that if we block the MMP-9 protein, the path between neurons will not open and the animal will not be able to remember important information. In the last few years, we have also shown that in humans, this protein is linked to addictions and schizophrenia', says Professor Leszek Kaczmarek.

In a healthy brain, MMP-9 is present in very small amounts: it is virtually undetectable, he adds. However, it is known that during brain injury there is an increase in the activity of this enzyme. And then it can then facilitate the unsealing of the blood-brain barrier, which allows the substances that later cause further damage to get into the brain. 'We also propose that the excess of MMP-9 locally causes excessive development of plasticity (i.e. changes in conductivity between neurons) in the brain. Synapses become excessively clear. And this may promote electrical discharges of neurons and the formation of an epileptic centre', Kaczmarek describes.

'We have shown that if a mouse is deprived of one gene responsible for the production of MMP-9, the mouse develops quite normally (although it has memory disorders, for example), but when brain damage occurs, it is resistant to post-traumatic epilepsy. And, in turn, excess MMP-9 in the brain of mice promotes the development of post-traumatic epilepsy', concludes Professor Leszek Kaczmarek.

Subsequent studies in mice have shown that if an MMP-9 inhibitor is administered within a few hours of the injury, it can stop the process leading to the development of epilepsy. The next step should be human trials.

'Our analyses show that the dose that will be effective will not cause harm to the patient. In humans, even a dose of 900 mg/kg of this inhibitor does not cause negative effects. On mice, administration of this enzyme at a much, much lower concentration of 9.5 mg/kg brought beneficial effects', the scientist says.

PAP - Science in Poland, Ludwika Tomala

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