U of M College of Pharmacy Study May Explain Why Some People with Epilepsy Do Not Respond to Medication

MINNEAPOLIS / ST. PAUL (April 21, 2008) -- A University of Minnesota College of Pharmacy researcher is the lead author on a study that found neurotransmitters released during epileptic seizures turn on a signaling pathway in the brain, which in turn increases production of a protein that could reduce medication entry into the brain.

“This may in part explain why approximately 30 percent of patients with epilepsy do not respond to anti-epileptic medications,” said Bjoern Bauer, Ph.D., assistant professor in the College of Pharmacy and lead author of the study, which will be published in the May 2008 issue of Molecular Pharmacology.

“Our work identifies how seizures increase production of a drug-transport protein in the blood brain barrier, known as P-glycoprotein, and suggests new therapeutic targets that could reduce resistance,” said David Miller, Ph.D., from the National Institute of Environmental Health Sciences Laboratory of Pharmacology and a co-author of the study.

The blood-brain barrier (BBB), which resides in brain capillaries, is a limiting factor in treatment of many central nervous system disorders. It is altered in epilepsy so that it no longer permits free passage of anti-epileptic drugs into the brain. P-glycoprotein forms a functional barrier in the BBB that protects the brain by limiting access of foreign chemicals.

“The problem is that the protein does not distinguish well between neurotoxicants and therapeutic drugs, so it can often be an obstacle to the treatment of a number of diseases, including brain cancer,” Miller said. Increased levels of P-glycoprotein in the BBB have been suggested as one probable cause of drug resistance in epilepsy.

Using isolated brain capillaries from mice and rats and an mouse model of epilepsy, the researchers found that glutamate, a neurotransmitter released during seizures, turns on a signaling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein. Increased P-glycoprotein expression was abolished by COX-2 inhibitors and in mice lacking COX-2. It has yet to be shown in animals or patients that targeting COX-2 will reduce seizure frequency or increase the effectiveness of anti-epileptic drugs.

“These findings provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders,” Bauer said. “Targeting blood-brain barrier signals that increase P-glycoprotein expression rather than the transporter itself suggests a promising way to improve the effectiveness of drugs that are used to treat epilepsy, though more research is needed before new therapies can be developed.”

The study was conducted by researchers at the University of Minnesota’s College of Pharmacy and Medical School, and the National Institute of Environmental Health Sciences (part of the National Institutes of Health), in collaboration with Heidrun Potschka’s laboratory at Ludwig-Maximilians-University in Munich, Germany.  It was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, and by grant from the German Research Foundation.

The College of Pharmacy, the only school of pharmacy in Minnesota, offers its program on the Twin Cities and Duluth campuses. Founded in 1892, the College of Pharmacy educates pharmacists and scientists and engages in research and practice to improve the health of the people of Minnesota and society. The college is part of the Academic Health Center, which is home to the University of Minnesota’s six health professional schools and colleges as well as several health-related centers and institutes. Learn more at www.pharmacy.umn.edu.

Contact: Amy Leslie, College  of Pharmacy, 612-624-7654
Sara Buss, Academic Health Center, 612-626-7037