Complex time-dependent alterations in the brain expression of different drug efflux transporter genes after status epilepticus

Frequent epileptic seizures or prolonged seizure activity (status epilepticus, SE) is known to increase the brain expression of drug efflux transporter genes and proteins, such as P-glycoprotein (Pgp) and members of the multidrug resistance protein (MRP) family, which might reduce brain levels of antiepileptic drugs and, therefore, be involved in drug resistance. However, the time course of alterations in Pgp or MRPs after seizures or SE is only incompletely known. This prompted us to study the time course of alterations in the expression of different efflux transporter genes (Mdr1a, Mdr1b, MRP1, MRP2, MRP5) at various times after a pilocarpine-induced SE in limbic brain regions, using quantitative real-time polymerase chain reaction (RT-PCR) (qPCR). Unexpectedly, between 6 and 24 h after onset of SE, genes encoding Pgp (Mdr1a, Mdr1b), Mrp1, and Mrp5 were downregulated in hippocampus, amygdala, or piriform cortex. This initial decrease in expression was followed by normalization and then increased expression, which became maximal 2 days after SE. One explanation for the initial decrease in transporter expression could be SE-induced acute inflammatory processes, because proinflammatory cytokines are known to suppress the expression of Pgp and other efflux transporters. To directly address this possibility, we quantified the hippocampal mRNA expression of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha, showing a marked SE-induced increase in these cytokines, which paralleled the decreased expression of efflux transporters. Taken together, these findings indicate that alterations in expression of drug efflux transporters after prolonged seizure activity are more complex than previously thought.