Abstract
Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01–3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02–1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001–0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08–0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5–0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.
Highlights
A prevailing theory of drug resistance in epilepsy attributes the failure of antiseizure medications (ASMs) to reach their targets to overexpression of efflux transporters, P-glycoprotein (ABCB1/MDR1), in epileptogenic brain tissue.[2−9] The expression of the other major blood−brain barrier (BBB) “gatekeeper”, the breast cancer resistance protein (ABCG2/BCRP), is unaffected by epilepsy.[10,11]
[18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) scans were conducted in eight patients, and images were analyzed visually before surgery
In each of the four patients who underwent resection of the anterior temporal lobe, amygdala, and hippocampus, both ABCB1/MDR1 and ABCG2/BCRP were less abundant in the focus of the epileptogenic zone than in the adjacent, less epileptogenic tissue
Summary
Drug-resistant epilepsy, defined as the failure of two or more appropriately chosen and used antiseizure medications (ASMs) to control seizures, is associated with increased risks of injuries, premature death, and reduced quality of life.[1,2] A prevailing theory of drug resistance in epilepsy attributes the failure of ASMs to reach their targets to overexpression of efflux transporters, P-glycoprotein (ABCB1/MDR1), in epileptogenic brain tissue.[2−9] The expression of the other major blood−brain barrier (BBB) “gatekeeper”, the breast cancer resistance protein (ABCG2/BCRP), is unaffected by epilepsy.[10,11] Additional efflux transporters, multidrug resistance-associated proteins (MRPs), have been shown to be upregulated in epileptogenic tissue, but their abundance in the human brain is much lower as compared to that of ABCB1/ MDR1 and ABCG2/BCRP.[12−14] Almost all of studies have comparatively and not absolutely quantified transporter protein expression in the epileptogenic focus within the human or rodent brain. Quantitative targeted proteomics, using liquid-chromatography-tandem mass spectrometry (LC−MS/MS) is a promising approach for predicting tissue drug concentrations by extrapolating in vitro studies to in vivo.[12,16] This method has been used before for quantifying transporter expression in brain tissue resected from epilepsy patients[13] and provided important data as to their absolute expression on isolated blood vessels.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
