Modulating P-glycoprotein to Enhance Neurodegenerative Drug Penetration of Brain

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DESCRIPTION (provided by applicant): In this proposal, we are investigating ways to increase the brain bioavailability of agents targeted against epilepsy and Alzheimer's disease, two common and devastating neurological disorders. We are exploring ways to reversibly modulate the activity of P-glycoprotein (P-gp) at the blood brain barrier (BBB). It has been shown in vivo that pharmacological inhibition of P-gp at the blood brain barrier by valspodar (PSC833) increased the uptake of the anti-epileptic agent phenytoin, a P-gp substrate, in brains. We propose to develop novel dimeric prodrug inhibitors of P-gp based on the therapeutic agents themselves. Once into the brain, these dimeric prodrugs will revert to the known approved therapeutic agent. We hypothesize that co-administration of the dimeric prodrug inhibitor in conjunction with therapeutic doses of the monomeric drug would serve to increase the level of the therapeutic agent in the brain and potentially lower the overall patient dose level. We believe that we have assembled a team of PIs with extensive experience to address each of the Specific Aims. Specific Aim 1: We will synthesize prodrug dimers of anti-epilepsy drugs (AEDs) (phenytoin, phenobarbital and lamotrigine), an anti-Alzheimer's disease drug (galantamine) and a potential anti- Alzheimer's disease agent (Gleevec) that are tethered via traceless linkers. Specific Aim 2: We will evaluate inhibition of P-gp transport by the prodrug dimers using various cell lines that overexpress P-gp or express P-gp at endogenous in vivo levels. Specific Aim 3: We will evaluate inhibition of P-gp transport of the fluorescent substrates daunomycin, calcein-AM, Bodipy-FL-verapamil and rhodamine 123 in isolated rat brain capillaries by the prodrug dimers and will use the therapeutic monomers as controls. At the completion of the proposed funding period, we will have dimeric prodrugs with activity against P-glycoprotein in brain endothelial cell and brain capillary models. The long term goals of this research will be to monitor brain penetration of AEDs and anti-Alzheimer's drugs in combination with the active prodrugs in an epileptic mouse model. Treating brain diseases is problematic because a number of drugs are not able to enter the brain. This lack of brain penetration is caused in part by a pump at the barrier to the brain that removes drugs before brain entry. This proposal seeks to remedy this problem by blocking the pump temporarily to allow drugs to pass into the brain. Completion of these studies has the potential to improve treatment of epilepsy and Alzheimer's disease.