Stiftung Tierärztliche Hochschule Hannover
Department of Pharmacology
Toxicology and Pharmacy

Bünteweg 17
30559 Hannover

Germany

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Project Leader

Prof. Dr. Wolfgang Löscher Phone: +49-(0)511-953-8720  Fax: +49-(0)511-953-8581  Contact

Project Staff

Dr. Marion Czapp Postdoc working on the project  Contact

Mr. Jens Bankstahl PhD student working on the project  Contact

Institute Presentation

Over the last 10 years, the group of W. Löscher has contributed significant studies substantiating the transporter hypothesis of drug resistance in epilepsy. The expression of multidrug transporters such as P-glycoprotein (P-gp) was determined in various animal models of temporal lobe epilepsy, showing overexpression of such transporters in brain capillary endothelial cells that form the blood-brain barrier. This overexpression was significantly more pronounced in antiepileptic drug (AED) resistant animals than in AED responsive animals. Several AEDs were shown to be substrates of P-gp and other efflux transporters at the blood-brain barrier. As a proof-of-principle of the transporter hypothesis, it was shown that AED resistance could be counteracted by inhibiting P-gp. In co-operation with groups in Munster and Bethel, Germany, peri-operative microdialysis was used to evaluate whether overexpression of efflux transporters also decreases AED brain levels in patients with drug resistant epilepsy. Currently, we examine whether overexpression of P-gp is also involved in drug refractory status epilepticus. The animal models developed by W. Löscher’s group are a unique tool for proof-of-principle studies of radioligands within the consortium.

In addition to mechanisms of pharmacoresistance in brain disorders such as epilepsy, other research topics of the group include (1) mechanisms of epileptogenesis and how to prevent  epilepsy by interfering with these mechanisms, and (2) development of new therapeutic strategies for treatment of epilepsy, including non-pharmacological approaches, such as deep brain stimulation and neurotransplantation.

Selected references

1. Löscher, W., Potschka, H. Drug resistance in brain diseases and the role of drug efflux transporters. Nature Rev. Neurosci 6:591-602, 2005.
2. Potschka H, Fedrowitz M,, Löscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J.Pharm.Exp.Ther. 306: 124-131, 2003
3. Brandt, C., Bethmann, K., Gastens, A., Löscher, W. The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol.Dis., 24: 202-211, 2006.
4. Rogawski, M. A. , Löscher, W. The neurobiology of antiepileptic drugs. Nature Reviews Neuroscience, 5: 553-564, 2004.
5. Rogawski, M. A., Löscher, W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nature Med., 10: 685-692, 2004.