EXPRESSION OF MULTIPLE DRUG RESISTANCE PROTEINS IN [quot]EPILEPTIC[quot] NEURONS
Abstract number :
F.06
Submission category :
Year :
2003
Submission ID :
3598
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Kelly M. Kight, Kerri L. Hallene, Nicola Marchi, Luca Cucullo, Annamaria Vezzani, Damir Janigro Department of Neurosurgery, The Cleveland Clinic Foundation NB-20, Cleveland, OH; Department of Neuroscience 20157, Mario Negri Research Institute, Milano, Ita
Approximately 20% of epileptic patients are resistant to anti-epileptic drug (AED) treatment. However, the mechanisms involved in multiple drug resistance (MDR) are not fully understood. Evidence has demonstrated an upregulation of MDR1 protein in endothelial cells and glia isolated from epileptic brain [1-3], yet systematic studies on neuronal expression are lacking. This is surprising since neurons are the ultimate target for AEDs. We investigated MDR1 expression in human [quot]epileptic[quot] neurons. We hypothesized that the presence of MDR in epileptic neurons was an indicator of cell protection against apoptosis.
We studied neurons and glia of resected tissue from medically intractable epileptic patients. Cells were identified as neurons or astrocytes by NSE or GFAP immunoreactivity. MDR1 expression was also visualized immunocytochemically. DNA integrity was estimated by nuclear staining with DAPI.
We analyzed a total of 264 NSE positive and 107 GFAP positive cells in 12 sections from 8 patients. Approximately 64% of neurons and 91% of glia expressed MDR1. Regardless of cell type, MDR1 afforded preservation of nuclear DNA integrity. 85% of glia and 66% of neurons expressing MDR1 were devoid of DNA damage.
Our results suggest a novel role for MDR1 independent of drug resistance but rather related to neuro/glia protection. Thus, vascular expression at the blood-brain barrier level may be responsible for reduced drug delivery to the epileptic brain, while parenchymal expression of multiple drug resistance protein may underlie the epileptic pathology.
1. Abbott,N.J., Khan,E.U., Rollinson,C., Reichel,A., Janigro,D., Dombrowski,S., and Dobbie,M.B.D.J., Drug resistance in epilepsy: the role of the blood-brain barrier. In: Ling V. (Ed.), Mechanisms of drug resistance in epilepsy: lessons from oncology, John Wiley, Chichester, UK, 2001, pp. 38-47.
2. Marroni,M., Agarwal,M., Kight,K., Hallene,K., Hossain,M., Cucullo,L., Signorelli,K., Namura,S., and Janigro,D., Relationship between expression of multiple drug resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes, Neuroscience, in press (2003).
3. Dombrowski,S., Desai,S., Marroni,M., Cucullo,L., Bingaman,W., Mayberg,M.R., Bengez,L., and Janigro,D., Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy, Epilepsia, 42 (2001) 1504-1507.
[Supported by: HL51614, NS43284, NS38195]