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

被引:141
作者
Feldmann, Maria [1 ,2 ]
Asselin, Marie-Claude [2 ]
Liu, Joan [1 ]
Wang, Shaonan [2 ]
McMahon, Adam [2 ]
Anton-Rodriguez, Jose [2 ]
Walker, Matthew [1 ,2 ]
Symms, Mark [1 ]
Brown, Gavin [2 ]
Hinz, Rainer [2 ]
Matthews, Julian [2 ]
Bauer, Martin [4 ]
Langer, Oliver [4 ,5 ]
Thom, Maria [1 ]
Jones, Terry [6 ]
Vollmar, Christian [1 ,3 ]
Duncan, John S. [1 ]
Sisodiya, Sanjay M. [1 ,3 ]
Koepp, Matthias J. [1 ,3 ]
机构
[1] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England
[2] Univ Manchester, Inst Populat Hlth, Wolfson Mol Imaging Ctr, MAHSC, Manchester, Lancs, England
[3] Epilepsy Soc, Gerrards Cross, Bucks, England
[4] Med Univ Vienna, Dept Clin Pharmacol, A-1090 Vienna, Austria
[5] Austrian Inst Technol, Hlth & Environm Dept, Seibersdorf, Austria
[6] PET Res Advisory Co, Wilmslow, Cheshire, England
基金
欧盟第七框架计划;
关键词
BLOOD-BRAIN-BARRIER; POSITRON-EMISSION-TOMOGRAPHY; DRUG-RESISTANCE; MULTIDRUG-RESISTANCE; IN-VITRO; RECEPTORS; SUBSTRATE; MODELS; HOC;
D O I
10.1016/S1474-4422(13)70109-1
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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)-[C-11]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[C-11]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)-[C-11]verapamil plasma-to-brain transport rate constant, K-1 (mL/min/cm(3)). Low baseline K-1 and attenuated K-1 increases after tariquidar correspond to high P-glycoprotein activity. Findings Between October, 2008, and November, 2011, we completed (R)-[C-11]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 K-1 corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0.031 vs 0.036 mL/min/cm(3); 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 K-1 after 2 mg/kg tariquidar, and 57.9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K-1 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.
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收藏
页码:777 / 785
页数:9
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