In order to protect against seizures, anti-epileptic drugs (AEDs) must pass from the bloodstream into the brain. However, unlike many other organs, the brain is protected against chemicals in the blood 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 permit the passage of important nutrients (such as glucose) into the brain, but prevent the entry of harmful toxins. There is now evidence that some of these pumps can also transport AEDs.
The most widely-studied BBB pump is known as P-glycoprotein (Pgp), and one of its roles appears to be the movement of certain AEDs out of the brain, to prevent their concentrations from becoming too high. In some cases, however, this outward movement means that insufficient AED is available in the brain for it to function effectively. Researchers in North Carolina have recently discovered a way to potentially overcome this hurdle. This has implications, not only for the treatment of epilepsy, but for other disorders of the central nervous system.
Using advanced microscopy in rodent models, the group succeeded in mapping an inflammatory signalling pathway that abolished Pgp transport activity, without affecting BBB function in any other way. They found that an important element of this pathway was a receptor known as sphingosine-1-phosphate receptor 1 (S1PR1), and that in brain capillaries, sphingosine-1-phosphate (S1P) (a potent signalling molecule) acted via S1PR1 to rapidly decrease Pgp transport activity. They also noted that this effect was completely reversible, i.e. when the S1P was removed, Pgp transport activity returned to normal.
The scientists explored these findings further by treating models with a drug called fingolimod, which is very similar in structure to S1P, and examining the effects on Pgp. Again, they found that Pgp transport activity was reversibly reduced.
In the final stage of their study, the team wanted to ensure that a reduction in Pgp transport activity did, in fact, lead to an increase in brain drug concentration. To do this, they selected three Pgp-transported drugs and attached a radioactive label to them, so that they could be tracked within the brain using microscopy. They took another group of models and pre-treated half with either fingolimod or S1P, and a short time later treated them all with one of the radio-labelled drugs. The half that was not pre-treated served as controls.
By quantifying the radio-labelling in the animals’ brains shortly after drug treatment, the researchers were able to compare whether the levels were higher in the fingolimod/S1P-treated or control groups. For each of the drugs, it was clear that brain levels were significantly increased in the fingolimod/S1P-treated models.
These findings suggest that compounds that mimic S1P could potentially enable some people respond to AEDs that they otherwise would not, thus helping to tackle the problem of AED resistance. If they are confirmed in further studies, taking a drug such as fingolimod alongside an AED may become option; however additional drugs bring an increased risk of unpleasant side-effects. The team’s next project will be to find out precisely how S1P reduces Pgp activity, as this is not clear. With this knowledge, it may be possible to develop drugs, including AEDs, which incorporate this action. We look forward to reading the outcomes of this and further studies.
πηγή http://www.epilepsyresearch.org.uk/
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