Elsevier

Neurobiology of Disease

Volume 39, Issue 2, August 2010, Pages 192-197
Neurobiology of Disease

Association between temporal lobe P-glycoprotein expression and seizure recurrence after surgery for pharmacoresistant temporal lobe epilepsy

https://doi.org/10.1016/j.nbd.2010.04.006Get rights and content

Abstract

Surgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporter that is overexpressed in a range of epileptogenic pathologies. We hypothesized that increased expression of P-glycoprotein in the epileptogenic temporal lobe might be a marker for recurrence of pharmacoresistant seizures postsurgery. We performed immunohistochemistry on temporal lobe tissues resected from 69 patients who underwent anterior temporal lobectomy for pharmacoresistant TLE with histopathological proven hippocampal sclerosis. P-glycoprotein expression was rated by three pathologists independently. Patients with seizure recurrence (n = 22) had greater number of positively stained capillaries (p = 0.001) and higher P-glycoprotein immunoreactive score in capillaries (p = 0.002) in the white matter of resected temporal lobe. The differences remained significant in multivariate analysis (p = 0.002 and 0.006, respectively). The results suggest that P-glycoprotein expression in temporal lobe may be associated with seizure recurrence after surgery for pharmacoresistant TLE.

Introduction

Despite appropriate drug treatment, 20–40% of patients with epilepsy continue to have seizures and are considered to have refractory or pharmacoresistant epilepsy (Kwan and Brodie, 2000, Schmidt and Löscher, 2005). Temporal lobe epilepsy (TLE) is the most common type of pharmacoresistant epilepsy (Semah et al., 1998), for which surgery in the form of anterior temporal lobectomy is a recommended treatment option in selected candidates (Engel et al., 2003). The most common pathological substrate identified in pharmacoresistant TLE is hippocampal sclerosis, the presence of which carries a higher probability of seizure-freedom after surgery (Radhakrishnan et al., 1998, Tonini et al., 2004, McIntosh et al., 2004, Spencer et al., 2005). However, despite careful selection, pharmacoresistant seizures recur in approximately one third of patients postsurgery, and no reliable clinical predictive factor has been identified (Hardy et al., 2003, Uijl et al., 2008). Identification of biological markers for seizure recurrence after surgery would be of great clinical value and may shed insights into the neurobiological basis underpinning pharmacoresistant epilepsy.

We hypothesized that P-glycoprotein expression in the epileptogenic temporal lobe might be one such marker. P-glycoprotein, encoded by the ABCB1 or MDR1 gene, is the “prototype” multidrug transporter belonging to the superfamily of ATP-binding cassette (ABC) proteins which are transmembrane proteins that extrude substrates from the cell against the concentration gradient. These proteins have been extensively studied in oncology because of their putative role in multidrug resistance to cancer chemotherapy (Gottesman et al., 2002). In the normal brain, P-glycoprotein is expressed at a basal physiologic level in capillary endothelial cells where it “pumps” a broad range of xenobiotics from intracellular space back to the capillary lumen, thereby maintaining the integrity of the blood–brain barrier and reducing the cerebral accumulation of substrate drugs. In a range of epileptogenic brain pathologies, including those associated with refractory TLE, upregulation of P-glycoprotein and other ABC multidrug transporters in capillaries, as well as novel or aberrant expression in glial and neuronal cells in some cases, have been reproducibly demonstrated (Tishler et al., 1995, Dombrowski et al., 2001, Sisodiya et al., 2002, Aronica et al., 2003, Aronica et al., 2004, Kubota et al., 2006, Ak et al., 2007). Such observations have lent support to the hypothesis that upregulation of P-glycoprotein (and other multidrug transporters) may play a mechanistic role in drug resistance in epilepsy (Kwan and Brodie, 2005, Löscher and Potschka, 2005). Given the common upregulation of P-glycoprotein in pathologies of refractory epilepsy we hypothesized that its expression might also correlate with surgical outcome. In this pilot study we compared P-glycoprotein expression levels and patterns by immunohistochemistry in the resected temporal lobe between patients with and without recurrent seizures after undergoing surgery for pharmacoresistant TLE. The study group was pathologically homogeneous, all having histopathologically proven hippocampal sclerosis, thereby minimizing potential confounding pathological factors in assessing the primary hypothesis.

Section snippets

Study patients and evaluation before surgery

Consecutive patients with pharmacoresistant TLE, with histopathology confirming hippocampal sclerosis, who underwent epilepsy surgery at the Royal Melbourne Hospital, Melbourne, Australia, between June 1993 and December 2005 were included in this study. All patients underwent a standard anterior temporal lobectomy by the same surgeon (A.H.K.) following a protocol-driven presurgical evaluation. The study was approved by the The Melbourne Health Human Research Ethics Committee.

The procedures for

Results

Sixty-nine (45 female) patients with histopathologically proven hippocampal sclerosis were included. Post-operative follow-up was a mean duration of 5.2 years (standard deviation 2.2 years). Forty-seven (68%) patients were seizure-free after surgery and 22 had recurrent seizures, all occuring while continuing to take antiepileptic drug therapy. Focal cortical dysplasia was found on histopathological examination of the resected temporal lobe in addition to hippocampal sclerosis in two patients,

Discussion

Approximately one third of the patients with hippocampal sclerosis-related medically refractory TLE in our series suffered recurrent pharmacoresistant seizures after surgery, which is similar to other reports. Confirming our previous analysis on a smaller sample (Kilpatrick et al., 1999), various preoperative clinical variables were not predictive of postsurgical seizure outcome (Table 1). The cohort provided a homogenous population who were otherwise identical in terms of the type and severity

Conflict of interest

None of the authors has any conflict of interest to disclose.

Acknowledgments

This work was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project no. CUHK4466/06M).

References (44)

  • E. Aronica et al.

    Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy

    Epilepsia

    (2004)
  • B. Bauer et al.

    Seizure-induced up-regulation of P-glycoprotein at the blood–brain barrier through glutamate and cyclooxygenase-2 signaling

    Mol. Pharmacol.

    (2008)
  • W.T. Beck et al.

    Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations

    Cancer Res.

    (1996)
  • L. Concha et al.

    White-matter diffusion abnormalities in temporal-lobe epilepsy with and without mesial temporal sclerosis

    J. Neurol. Neurosurg. Psychiatry

    (2009)
  • S.M. Dombrowski et al.

    Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy

    Epilepsia

    (2001)
  • Engel, J. Jr., Wiebe, S., French, J., Sperling, M., Williamson, P., Spencer, D., Gumnit, R., Zahn, C., Westbrook, E.,...
  • J.L. Fleiss et al.

    The measurement of interrater agreement

  • M.M. Gottesman et al.

    Multidrug resistance in cancer: role of ATP-dependent transporters

    Nat. Rev. Cancer

    (2002)
  • S.G. Hardy et al.

    Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis

    Epilepsia

    (2003)
  • M.J. Hennessy et al.

    Failed surgery for epilepsy. A study of persistence and recurrence of seizures following temporal resection

    Brain

    (2000)
  • M.J. Hennessy et al.

    Predictors of outcome and pathological considerations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions

    J. Neurol. Neurosurg. Psychiatry

    (2001)
  • M. Hildebrandt et al.

    White matter angiopathy is common in pediatric patients with intractable focal epilepsies

    Epilepsia

    (2008)
  • Cited by (32)

    • Protein expression of P-glycoprotein in neocortex from patients with frontal lobe epilepsy

      2022, Epilepsy Research
      Citation Excerpt :

      The neuronal P-gp expression has been associated with increased cellular excitability (Auzmendi et al., 2013; Hoffman et al., 1996; Wadkins and Roepe, 1997) and thus, could play a central role in epileptogenesis (Czornyj et al., 2021; Lazarowski et al., 2007). Surgical outcomes differ in patients with temporal lobe epilepsy depending on the expression of P-gp (Kwan et al., 2010). Probably, the different surgical outcomes among tumor-related FLE and posttraumatic FLE are also related to differences in P-gp expression.

    • ABC transporters in drug-resistant epilepsy: mechanisms of upregulation and therapeutic approaches

      2019, Pharmacological Research
      Citation Excerpt :

      The increases in the efflux rate constant significantly correlated with Abcb1 upregulation measured by immunohistochemistry. To the best of our knowledge, one of the few clinical studies regarding this topic was performed by Kwan et al., who examined temporal lobe tissue from patients who underwent lobectomy for drug-resistant TLE [135]. They noticed increased capillary staining of ABCB1 in patients who had seizure relapses compared to those who did not have seizures after surgery.

    • In vitro transport assays of rufinamide, pregabalin, and zonisamide by human P-glycoprotein

      2014, Epilepsy Research
      Citation Excerpt :

      Pgp inhibition or knockout in animals indicates that Pgp at the normal BBB reduces phenytoin penetration of the brain by nearly half (Loscher et al., 2011). At epileptic foci, Pgp is overexpressed (Kwan et al., 2010; Aronica et al., 2012; Feldmann et al., 2013), further reducing phenytoin penetration by about 30% (Loscher et al., 2011). Despite the ability of Pgp to overcome high passive permeability of substrate AEDs, measuring efflux of such drugs across monolayers of cultured cells is challenging because, when an AED is added to one side of a monolayer, the increase in concentration on the other side of the cells due to Pgp efflux is partly masked by passive diffusion across the membrane down the concentration gradient.

    View all citing articles on Scopus
    View full text