Molecular mechanisms of drug resistance in status epilepticus

Status epilepticus (SE) is a neurologic emergency, characterized by continuous or intermittent seizures without full recovery of consciousness between seizures, which can result in death or neurologic sequelae. In about onethird of patients, SE is unresponsive to sequential treatment with firstand second-line antiepileptic drugs (AEDs). The two most important variables that influence the response of SE to AEDs are the underlying etiology and the duration of SE (Neligan & Shorvon, 2008). With respect to etiology, acute structural brain disorders (e.g., encephalitis, stroke, and trauma) resulting in SE in previously nonepileptic patients are particularly likely to be refractory. Conversely, in cases of acute SE in previously nonepileptic patients, for which no etiology is found, the outcome is usually much better. With respect to duration of SE, the longer the seizure persists (typically >1 h), the more likely is the seizure to be unresponsive to AED therapy, the higher is the mortality, and the worse is the prognosis in survivors. Similar observations have been reported in rat models of SE. In rats, SE can be induced with chemical agents or by electrical stimulation. Chemical models of SE include systemic administration of the convulsants kainic acid or pilocarpine, whereas electrical models include hippocampal or amygdala stimulation via depth electrodes. In such models, seizures rapidly become self-sustaining and continue long after the withdrawal of the convulsive stimulus. Various molecular and functional changes are thought to play a role in the transition from single seizures to selfsustained SE and in the development of time-dependent pharmacoresistance in rat SE models (Chen & Wasterlain, 2006; Wasterlain & Chen, 2008). These changes include alterations in the functional properties of hippocampal c-aminobutyric acid (GABA)A receptors and enhanced trafficking of GABAA receptors (or receptor subunits) from the synaptic membrane to the cytosol, resulting in a loss of GABA-mediated inhibition. At the same time, glutamate receptor subunits, including alpha-amino3-hydroxy-5-methyl-4-isoxazole propionate acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor subtypes, move to the synaptic membrane where they form additional excitatory receptors. These changes are likely to explain progressive resistance to AEDs acting on GABAA receptors, whereas anticonvulsant NMDA or AMPA antagonists remain highly effective in terminating SE (Wasterlain & Chen, 2008). These findings, however, do not easily explain resistance to AEDs, such as phenytoin, that do not primarily act via GABA receptors. It is conceivable that AED targets other than GABA or glutamate receptors are also affected by sustained seizure activity. For instance, molecular and functional changes in voltage-dependent sodium channels, which are targets of phenytoin and various other major AEDs, have been found after a pilocarpine-induced SE in rats (Ellerkmann et al., 2003; Remy & Beck, 2006). Furthermore, a decrease in surface expression of potassium channels has been described after prolonged SE (Lugo et al., 2008). Another explanation for the progressive loss of AED efficacy with ongoing SE activity would be increased expression of drug efflux transporters such as P-glycoprotein (Pgp) at the blood–brain barrier, which would decrease brain concentrations of AEDs that are substrates for Pgp (Lçscher, 2007). However, recent experiments in two rat models of SE did not result in any evidence supporting this possibility (Bankstahl & Lçscher, 2008; Kuteykin-Teplyakov et al., 2009). Pgp expression at brain capillary endothelial cells was not increased during or shortly after SE, but only 2 days following SE. This was substantiated by studying the mRNA expression of the genes (Mdr1a, Mdr1b) encoding for Pgp in rats. Furthermore, the selective Pgp inhibitor, tariquidar, did not counteract resistance of a pilocarpine-induced SE to phenobarbital or phenytoin (Bankstahl & Lçscher, 2008). In our hands, the only effective treatment for terminating a pilocarpine-induced SE was a combination of Address correspondence to Dr. Wolfgang Lçscher, Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, B nteweg 17, D-30559 Hannover, Germany. E-mail: wolfgang.loescher @tiho-hannover.de