p53 and Multidrug Resistance Transporters in the Central Nervous System

Multidrug resistance (MDR) is a complication that is often seen during the treatment of cancer and epilepsy. This resistance has been attributed to an increased expression of ATP-binding cassette (ABC)-membrane efflux transporters in brain. Expression of these transporters, in particular P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), have been shown to be regulated by the tumor suppressor gene p53 in that p53 mutations can lead to transporter induction. On the other hand, increased p53 expression in the brain is associated with neuronal cell death via apoptosis. Epileptic brain has been shown to regulate the MDR genes in a manner similar to tumor cells. Seizures have also been shown to precipitate a generalized acute inflammatory response and cytokine release within the central nervous system (CNS). The overall phenomenon of cell cycle arrest, apoptosis, and induction of MDR in epilepsy may be linked through common signaling pathways activated by these stimuli. Complexities in the development and regulation of MDR within the CNS underscore the need to delineate the molecular pathways involved. Ultimately, this knowledge may be used in the development of novel therapeutics in refractory epilepsy or malignancies.