Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia

Abstract

Recent arouse of interest indicated that drug resistant proteins are markedly over-expressed in the epileptogenic tissue and they may be responsible for the one-third of the epileptic patients who were refractory to anti-epileptic drugs (AEDs). Since several AEDs may act as substrates for these drug resistant proteins, the enhanced function of such proteins may increase drug extrusion, resulting in inadequate response to drug therapy in patients with epilepsy. We studied expression of the multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) in the epileptic tissues resected surgically in 28 patients with focal cortical dysplasia (FCD) by immunohistochemistry. The results were compared with 10 normal necropsy brain tissues. Normal brain showed no MDR1 expression in neurons and astrocytes, while MRP1 expression was very weak, which were encountered in a few samples. MDR1 expression was mainly localized on the vascular endothelial cells. In contrast to normal brain, we found intense MDR1 and MRP1 expression in both neurons and reactive astrocytes in the vast majority of dysplastic tissues. The majority of the dysplastic neurons demonstrated moderate to strong MRP1 immunoreactivity. Endothelial cells showed both MDR1 and MRP1 expression in the majority of the specimens studied. Multidrug transporters are over-expressed in the epileptogenic zone in patients with FCD. These results are concordant with previous studies, in which over-expression of multidrug proteins were shown in epileptogenic brain tissue in patients with FCD, that the over-expression of drug transport proteins in tissue from patients with refractory epilepsy may explain one possible mechanism for drug resistant in these pathologies.

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

“…Subsequently, increased levels of P-gp protein expression have also been observed in the brain capillary endothelium of resected brain tissue from patients with refractory epilepsy, where P-gp overexpression was localized to the luminal membrane of the brain capillary endothelium by immunohistochemistry (80, 90). P-gp overexpression was also detected in astrocytes and/or dysplastic neurons in common pathological causes of refractory epilepsy, including dysembryoplastic neuroepithelial tumors (DNT), HS, and focal cortical dysplasia (FCD) (32, 84, 88, 91–93). …”

Substrates and Inhibitors of Human Multidrug Resistance Associated Proteins and the Implications in Drug Development

“…Moderate levels of MRP1 are also expressed in a cell specific manner in the brain, mainly in microvascular endothelial cells but also in astrocytes and microglia, as well as the blood-brain barrier (BBB) and the choroid plexus of the blood cerebrospinal fluid barrier [32][33][34][35][36][37][38]. Because most of these tissues belong to the defense lines of the body, it is somewhat unexpected that MRP1/ABCC1 is barely detectable in adult human liver, but in proliferating hepatocytes in the regenerating regions of the liver after tissue damage and liver cancer cell lines such as HepG2, its expression is considerably elevated to a high level [39].…”

Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

“…In the field of epileptology, studies in rodent and human brain capillaries have revealed that glutamate can upregulate P-glycoprotein via an N-methyl-D-aspartic acid (NMDA) receptor/cyclooxygenase-2 signaling pathway (Bauer et al, 2008b;Zibell et al, 2009;van Vliet et al, 2010;Avemary et al, 2013). Considering the excessive extracellular glutamate concentrations reached during epileptic seizures, this signaling pathway explains the overexpression of P-glycoprotein, which has been repeatedly found in the epileptic brain (Tishler et al, 1995;Thomas et al, 2003Thomas et al, , 2004Thomas et al, , 2005Aronica et al, 2004;Kubota et al, 2006;Ak et al, 2007).…”