Targeting anti-epileptic drug therapy without collateral damage: nanocarrier-based drug delivery.

Commentary Medically refractory epilepsy is estimated to occur in about 500,000 individuals of the nearly 3 million in the United States with epilepsy. Medication resistance in epilepsy is due, in part, to tolerance related to molecular mechanisms that eliminate, or minimize the persistence of antiepileptic drug (AED) molecules in the brain. Currently, drug discovery for CNS disorders is almost exclusively limited to small molecular weight lipophilic molecules that can cross the blood brain barrier (BBB), and blood-cerebral spinal fluid barrier (BCSFB). This simple prerequisite eliminates a majority of potential AED molecule candidates early in the drug discovery process. The recent review by Haque et al. offers a comprehensive up-to-date understanding of the strategies that facilitate drug efficacy by focusing on creative drug delivery mechanisms rather than drug discovery. This article reviews the challenges of overcoming the array of active and passive transporter systems at the BBB and BCSFB that shuttle drug molecules toward and away from neural tissue. The authors compare drug molecule transport across the BBB and neural cell membranes in a number of disorder-based platforms including epilepsy. These transporters play the role of " gatekeepers " limiting access of molecules to the brain. Specifically, several transporter superfamilies mediate access of therapeutic drug molecules to the brain. The adenosine triphosphate binding cassette (ABC), and solute carrier (SLC) transporters comprise the two major known drug superfamily transporters in the brain. P-glyco-protein is the most extensively studied BBB transporter of the ABC family. P-glycoprotein in animal models can play a role in eliminating antiepileptic drug molecules, such as phenytoin, phenobarbital (1), and levetiracetam. However, the extent to which this transporter is involved in drug tolerance in humans remains unclear. The SLC transporter superfamily includes the organic anion transporters localized on neurons themselves. This system probably plays a significant role in eliminating valproic acid. Also noteworthy, is an associated monocarboxyl-ate transporter, associated with CNS uptake of medium-chain fatty acids that play a dominant role in transporting valproic acid into the brain. The system L-transporters bidirectionally transport gabapentin and pregabalin. In addition, the multi-drug resistance-associated proteins (MRP) found at the BBB and BCSFB can restrict brain entry of phenytoin (2). Manipulating these transporter gatekeepers can potentially increase the entry and persistence of drug molecules in the brain. Haque et al. focus on reviewing the growing field of nan-otechnology utilized as innovative tools to deliver drugs across the BBB, and through the brain parenchyma. …