Epilepsia, 45(5):441–451, 2004 Blackwell Publishing, Inc. C  2004 International League Against Epilepsy Expression and Cellular Distribution of Multidrug Resistance–related Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy ∗ †Eleonora Aronica, †‡Jan A. Gorter, ∗ Marja Ramkema, ∗ Sandra Redeker, §Filiz ¨ Ozbas-Ger¸ cerer, †‡Edwin A. van Vliet, ‖George L. Scheffer, ‖Rik J. Scheper, ‖Paul van der Valk, ¶Johannes C. Baayen, and ∗ Dirk Troost ∗ Departments of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, †Stichting Epilepsie Instellingen Nederland, Heemstede, and ‡Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands; and §Department of Medical Biology and T ¨ UBITAK DNA/Cell Bank, Faculty of Medicine, Hacettepe University, Ankara, Turkey; and Departments of // Pathology and ¶ Neurosurgery, Free University Medical Center, Amsterdam, The Netherlands Summary: Purpose: This study investigated the cellular dis- tribution of different multidrug resistance (MDR)-related pro- teins such as P-glycoprotein (P-gp), the multidrug resistance– associated proteins (MRP) 1 and 2, and the major vault protein (MVP) in normal and sclerotic hippocampus of patients with medically refractory mesial temporal lobe epilepsy (MTLE). Methods: Single- and double-label immunocytochemistry was used on brain sections of control hippocampus and of hip- pocampus of refractory MTLE patients. Results: In TLE cases with hippocampal sclerosis (HS), all four MDR proteins examined that had low or no expression in control tissue were upregulated, albeit with different cellular distribution patterns. P-gp immunoreactivity (IR) was observed in astrocytes in regions with diffuse reactive gliosis. In 75% of HS cases, strong P-gp IR was detected in blood vessels, with prominent endothelial labeling. Reactive astrocytes displayed low MRP1 IR. However, glial MRP1 expression was noted in glial endfoot processes around blood vessels. Neuronal MRP1 expression was observed in hypertrophic hilar neurons and in a few residual neurons of the CA1 region. Hippocampal MRP2 ex- pression was observed in the large majority of HS cases in blood vessels. Hypertrophic hilar neurons and blood vessels within the sclerotic hippocampus expressed major vault protein (MVP). Conclusions: These findings indicate that MDR proteins are upregulated in concert in the hippocampus of patients with refractory MTLE, supporting their role in the mechanisms underlying drug resistance. The specific cell-distribution pat- terns within the sclerotic hippocampus suggest different cel- lular functions, not necessarily linked only to clinical drug resistance. Key Words: Epilepsy—Hippocampal sclerosis— Major vault protein—Multidrug resistance–associated protein— P-glycoprotein. In human epilepsy, the failure to respond to anticonvul- sant drug (AED) treatment is a crucial clinical problem, because in ∼30% of epilepsy patients, seizures persist de- spite appropriate polytherapy at maximal tolerated doses (1,2). The basis of this multidrug resistance is still elusive but is likely to be multifactorial. Resistance to pharmaco- logic treatment with a broad range of AEDs with different mechanisms of action, but common physical characteris- tics, supports the involvement of nonspecific mechanisms responsible for different types of clinical drug resistance (for example, as seen with drug resistance to cytostatic drugs in cancer treatment) (3,4). One possible general Accepted January 13, 2004. Address correspondence and reprint requests to Dr. E. Aronica at De- partment of (Neuro) Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: e.aronica@amc. uva.nl mechanism to account for this medical intractability is the inadequate drug concentration in the epileptogenic areas. In recent years, attention has been focused on multidrug transporters such as P-glycoprotein (P-gp) and the fam- ily of multidrug resistance–associated proteins (MRPs) (reviewed in 3,5–7). Subcellular particles called vaults, possibly involved in sequestration and compartmentaliza- tion of drugs away from the intracellular target, also may play a role in clinical drug resistance (8,9). Overexpres- sion of multidrug resistant (MDR)-related proteins has been recently shown in several causes of human refrac- tory epilepsy (10–15). Hippocampal sclerosis (HS) constitutes the most fre- quent neuropathologic finding in adult patients with med- ically intractable temporal lobe epilepsy (TLE) (2). Previ- ous studies analyzed HS together with other lesions asso- ciated with intractable epilepsy, focusing mainly on the 441