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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS043284-01
Application #
6463319
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Margaret
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$316,350
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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