Ex-vivo studies: WP03 and WP06

Over-expression of P-gp has been implicated as a cause of drug resistance in a number of CNS diseases. However, we do not know whether over-expression occurs de novo or as a result of exposure to drugs or for example in epilepsy, as result of uncontrolled seizures. Inhibition of transport by MDR1 depends on a number of factors including genetic polymorphisms within the ABCB1 gene. There is a great deal of overlap in the specificity of transport inhibitors for different members of the ABC family of transporters. Ex-vivo studies will identify the mechanisms of multidrug transporter function at the cellular level with in-vitro characterisation and identification of compounds that overcome inhibition of drug entry across the BBB. (WP03)

The sine qua non for transporters to have a role in mediating resistance is that they have an appropriate anatomical distribution in human brain tissue. Complex, at times diverging neuropathological and molecular biological findings illustrate the complexity of any potential P-gp involvement in resistance to CNS xenotoxins, and the absolute need to evaluate transporter distribution, quantity, and evidence of BBB dysfunction in diseased human brain tissue. Ex-vivo studies will determine anatomical distribution of transporter proteins in brain tissue from patients with epilepsy, and dementia, and determine its impact on drug resistance. (WP08)