Drug Resistance in Cortical and Hippocampal Slices from Resected Tissue of Epilepsy Patients: No Significant Impact of P-Glycoprotein and Multidrug Resistance-Associated Proteins

Abstract

Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.

Adenosine A1 receptor–mediated suppression of carbamazepine‐resistant seizure‐like events in human neocortical slices

“…A upper trace). Moreover, pharmacoresistance of SLEs was independent of induction protocol in temporal cortex, dentate gyrus, and subiculum . As exemplified here with CBZ, reproducing previous findings from our laboratory, we suggest that pharmacoresistance is preserved in most of our slices.…”

“…Epileptiform events with durations >5 s were classified as SLEs and typically were biphasic with a tonic‐like and subsequent clonic‐like activity superimposed on a slow negative DC shift (Fig. A; see also). SLEs in the control group were stable for at least 90 min regarding incidence and event duration (n = 13 slices, six patients; Fig.…”

“…Human temporal neocortex specimens were obtained as described previously . In brief, patients with mesial temporal lobe epilepsy (MTLE) received presurgical evaluation in the Epilepsy‐Center Berlin‐Brandenburg.…”

“…Studies from our lab and other labs have previously shown that slice preparations from resected human tissue are suitable to study pharmacologic properties of induced epileptiform activities . Generally, resistance of seizure‐like events (SLEs) to common AEDs like carbamazepine (CBZ), valproate (VPA), and phenytoin (PHT) is preserved in slice preparations of hippocampal and neocortical tissue from pharmacoresistant patients, thereby providing a model of pharmacoresistant epilepsy.…”

Carbamazepine modulates the spatiotemporal activity in the dentate gyrus of rats and pharmacoresistant humans in vitro

“…) or had no effect at all in hippocampal and cortical slices (Sandow et al. ). Reckziegel and colleagues reported a reduced maximal Na + current amplitude with increasing CBZ concentration (15–320 μ mol/L) and a saturated shift in the voltage‐dependent steady‐state inactivation in the hyperpolarizing direction in human DG cells acutely isolated from the focal epileptic area for CBZ concentrations of 100 μ mol/L and higher (Reckziegel et al.…”