MINNEAPOLIS, April 23, 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.