The blood-brain barrier effectively shields the brain parenchyma from a number of potentially neurotoxic substances. This is achieved in virtue of expression of specific zipper-like proteins that join neighboring endothelial cells. In addition to this cellular barrier, endothelial cells also express multiple drug resistance (MDR)-related proteins that act as extruders of a number of drugs that would otherwise significantly contribute to treatment of a number of central nervous system disorders including epilepsy. We have shown upregulation of MDR gene expression in endothelial cells isolated from human epileptic vs. non-epileptic brain. We have also unveiled an abnormal pattern of MDR expression in 1 """"""""epileptic"""""""" glia. To further our knowledge on the mechanisms involved in the development of pharmacoresistance to antiepileptic drugs (AED) we propose: 1) To study patterns of MDR gene expression across different epileptic pathologies compared to non-epileptic brain; 2) To determine the cellular distribution of MDR gene products in epileptic compared to non-epileptic cortex; 3) To test the hypothesis that breakdown of the blood-brain barrier is an early event leading to pharmacoresistance and expression of MDR in perivascular glia; and 4) To determine the AED permeability across and """"""""epileptic"""""""" blood-brain barrier model compared to non-MDR expressing endothelial cells and glia. We propose to use a multidisciplinary approach combining molecular biology, protein analysis and functional studies; these studies will be performed on freshly isolated surgical specimens characterized by their epileptogenic (or normal) electrical activity by a team of neurosurgeons and neurologists. The long-term goal of this laboratory is to understand interactions between neuronal and non-neuronal cells in health and disease. In particular, we are investigating how changes in blood-brain barrier function may drive glia and neurons into an """"""""epileptic"""""""" phenotype.
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