TiHo Bibliothek elib - Tierärztliche Hochschule Hannover

SUMMARY
SUMMARY
Dana Alms
Induction of multidrug transporters by antiepileptic drugs and known inducers
and their transport in brain capillary endothelial cells of the blood-brain barrier
of different species
Approximately 50 million peoples are affected by epilepsies (DUNCAN et al.
2006) and efficient therapies are of great interest. In most cases patients are treated
with antiepileptic drugs (AEDs). But one third of the epileptic patients is not seizurefree
under the AED treatment (KWAN & BRODIE 2000). Reasons for the
phenomenon of pharmacoresistance are until now not fully understood. According to
the multidrug transporter hypothesis, one explanation for pharmacoresistance, an
overexpression of multidrug-resistance transporters (MDTs) at the blood-brain barrier
(BBB) leads to an increased efflux of AEDs back to the blood and consequently
inadequate concentrations in the epileptic focus. TISHLER et al. (1995) first
described correlations between overexpression of multidrug-resistance transporter
proteins and pharmacoresistance by detection of the well investigated MDT P-
glycoprotein (Pgp) in epileptic tissue. Furthermore, studies provided evidence that
several AEDs are transported by Pgp in therapeutic concentrations (LUNA-TORTÓS
et al. 2008 und 2009). This would explain low brain concentration of these
substances. So far, only the antiepileptic drug phenytoin was investigated regarding
the transport by Pgp in human brain capillary endothelial cells (CUCULLO et al.
2007).
One object of the thesis was the investigation of the immortalized human brain
endothelial cell line hCMEC/D3 as an in vitro model of the BBB and the transport of
AEDs by Pgp in cells of human origin. But because of an insufficient tightness of the
cell monolayers, immortalized brain endothelial cells are considered to be not
suitable for transport studies (DELI et al. 2005; ROUX & COURAUD 2005).
Therefore, primary rat brain endothelial cells were dissected and utilized for transport
assays to detect Pgp-specific transport.
The thesis dealt with the MDT hypothesis, the associated overexpression of
MDTs and the establishment of a human cell line in a transwell model. The initial
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