What causes drug-resistant epilepsy?

Grant round winners 2010

Anti-epileptic drugs (AEDs) need to pass from the blood into the brain in order to protect against seizures. However, unlike many other organs, the brain is protected against chemicals in the bloodstream by a complex structure known as the blood-brain barrier (BBB). AEDs rely on a variety of mechanisms to help them cross the BBB, not all of which are understood.

The cells of the BBB have a range of different pumps, which allow important nutrients such as glucose to pass into the brain, but prevent the entry of harmful toxins. It now seems that some of these pumps can also transport AEDs. P-glycoprotein (Pgp) is the most widely studied BBB pump and part of its role appears to be the movement of certain AEDs out of the brain, to prevent their concentrations from getting too high.

Approximately one third of people with epilepsy are resistant to AEDs, i.e. they do not respond to drug treatment and continue to experience seizures. Some scientists believe that a possible explanation for this is an increased number of Pgp-type pumps at the BBB, which transport larger amounts of AEDs out of the brain than normal and make the drugs less effective.

What about the other pumps at the BBB? What are their roles in AED transport and resistance?

Dr Graeme Sills and colleagues, from the University of Liverpool, have been awarded £98,760 over 36 months to carry out a project entitled Antiepileptic drug transport at the blood-brain barrier; more than just P-glycoprotein, in which they will investigate a different family of pumps known as the SLC transporters. They will examine the effect of individual members of this protein family on AED transport into and out of the brain by growing different types of blood vessel and brain cell in the laboratory and instructing them (using genetic manipulation) to make a particular SLC pump. The team will then assess the ability of these pumps to transport six widely used AEDs, phenytoin, carbamazepine, sodium valproate, lamotrigine, topiramate, and levetiracetam, under different conditions. They will also use chemicals to manipulate specific pumps and look at the effect of those chemicals on AED concentrations.

Once they have established which members of the SLC family are able to transport AEDs, Dr Sills’ group will assess the activity of these pumps in animals with epilepsy and examine whether altering the activity of the pumps can increase the amount of AEDs in the brain and improve seizure control.

This project will complement the ongoing studies into Pgp, and will hopefully give scientists a clearer understanding of both AED transport across the BBB and the mechanisms of drug resistance in epilepsy. If successful, this research could lead to the development of a new drug that modifies the effect of pumps at the BBB and increases the concentration of AEDs in the brain. This might allow people who would otherwise be resistant to current AEDs an opportunity for effective seizure control.

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