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.

Previous studies have shown that Pgp transport in animal brains is rapidly reduced by a signaling molecule called tumor necrosis factor-alpha (TNF-alpha). This is released by several different cells of the immune system in response to infection, and it acts via a type of enzyme known as protein kinase C (PKC).

PKC is a family of enzymes that includes PKC-alpha, PKC-beta I, PKC-beta II and PKC-gamma, and these all function in slightly different ways. Researchers at the National Institute of Environmental Health Sciences, in North Carolina, recently examined the relationships between TNF-alpha, PKC-beta I, PKC-beta II and Pgp activity in animal models. They used the compound [(3)H]-verapamil, which can be transported by Pgp, to assess Pgp function.

The group found that if the function of PKC-beta I and II was blocked (by a PKC inhibitor), TNF-alpha was no longer able to reduce Pgp activity. However they also noticed that if a substance known as dPPA (a PKC activator) was used to activate PKC-beta I and II, there was a similar reduction in Pgp activity to that produced by TNF-alpha.

Closer examination of dPPA function revealed that it activated PKC-beta I, but not PKC-beta II. When dPPA was administered via the carotid artery (the major artery in the neck that supplies blood to the brain), [(3)H]-verapamil levels began to increase in the brain (the rate at which it was shunted out of the brain by Pgp was greatly reduced). Replacing [(3)H]-verapamil with a typical AED should, in theory, achieve the same result.

These results are exciting, because if they are replicated in humans, drugs that activate PKC-beta I at the BBB could be developed to enhance the delivery of AEDs and other drugs to the brain and improve their efficacy.

Read more here

This year Epilepsy Research UK awarded a grant to Dr Graeme Sills, at the University of Liverpool, to study other types of transport at the BBB. You can read more about his project here.