P-glycoprotein expression and function in patients with temporal lobe epilepsy: A case-control study

Feldmann, M., Asselin, M.-C., Wang, S., McMahon, A., Anton-Rodriguez, J., Walker, M., Symms, M., Brown, G., Hinz, R., Matthews, J., Bauer, M., Langer, O., Thom, M., Jones, T., Vollmar, C., Duncan, J.S., Sisodiya, S.M., Koepp, M.J. and Liu, J.Y.W. 2013. P-glycoprotein expression and function in patients with temporal lobe epilepsy: A case-control study. The Lancet Neurology. 12 (8), pp. 777-785. https://doi.org/10.1016/s1474-4422(13)70109-1

TitleP-glycoprotein expression and function in patients with temporal lobe epilepsy: A case-control study
TypeJournal article
AuthorsFeldmann, M., Asselin, M.-C., Wang, S., McMahon, A., Anton-Rodriguez, J., Walker, M., Symms, M., Brown, G., Hinz, R., Matthews, J., Bauer, M., Langer, O., Thom, M., Jones, T., Vollmar, C., Duncan, J.S., Sisodiya, S.M., Koepp, M.J. and Liu, J.Y.W.
Abstract

Background
Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood–brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy.

Methods
We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[11C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[11C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[11C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm3). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.

Findings
Between October, 2008, and November, 2011, we completed (R)-[11C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm3; p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001).

Interpretation
Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.

Funding
EU-FP7 programme (EURIPIDES number 201380).

JournalThe Lancet Neurology
Journal citation12 (8), pp. 777-785
ISSN1474-4422
Year2013
PublisherElsevier
Digital Object Identifier (DOI)https://doi.org/10.1016/s1474-4422(13)70109-1
Web address (URL)http://www.scopus.com/inward/record.url?eid=2-s2.0-84880325687&partnerID=MN8TOARS
Publication dates
Published2013
Published online18 Jun 2013

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