Unlocking the barrier
Epilepsy is the most common chronic neurological disease and characterized by recurrent seizures. Anticonvulsant medication can prevent seizures. However, up to 40 percent of patients respond poorly if at all to these substances. Impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure. An international cooperation under the lead of Professor Heidrun Potschka at the Department of Veterinary Medicine at the Ludwig-Maximilians-Universität (LMU) München has now identified molecular mechanisms which can contribute to this kind of drug resistance. As reported in the most recent issue of Molecular Pharmacology, epileptic seizures result in an increased production of P-glycoprotein. This is a known drug efflux pump and could prevent epileptic medication from entering the brain – therefore rendering it ineffective. By blocking the underlying molecular pathway different drugs could become functional again: in epilepsy and possibly also in strokes, infections like HIV and other diseases of the central nervous system.
“Seizures are known to be associated with the release of high glutamate concentrations” says Potschka. “This neurotransmitter in turn initiates a signalling cascade involving inflammatory mediators which results in an increased production of P-glycoprotein.” As a drug efflux pump the molecule is part of the so-called blood-brain barrier, a physiological structure which limits the passage of foreign chemicals into the brain – friend and foe alike. But there might be a basis for practical strategies to overcome or prevent pharmacoresistance readily available: Inhibitors of cyclooxygenase-2 are widely used for their anti-inflammatory activity. In experiments these drugs lower the production of P-glycoprotein in response to seizure activity. If they prove successful in humans at least some of the many sufferers from epilepsy may benefit from a more effective therapy. And other patients as well: Studies show that the same molecular mechanisms might cause drug resistance in many diseases of the central nervous system, ranging from stroke, trauma and brain tumors to infections like HIV.
“Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling”,
Björn Bauer, Anika M.S. Hartz, Anton Pekcec, Kathrin Toellner, David S. Miller and Heidrun Potschka,
Molecular Pharmacology, May 2008, vol. 73, nr. 5, pp. 1444-1453
Professor Dr. Heidrun Potschka
Department of Veterinary Medicine at LMU Munich
Tel.: 089 / 2180-2663
Fax: 089 / 2180 -16556