NIEHS, U. Minn. study may lead to improved epilepsy treatments

Researchers from the National Institute of Environmental Health Sciences (NIEHS) and the University of Minnesota have gained new insight into one of the most puzzling aspects of epilepsy treatment: why some epileptics fail to respond to anti-epileptic medications.

Amy Swinderman
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RESEARCH TRIANGLE PARK, N.C.—Researchers from the National Institute of Environmental Health Sciences (NIEHS) and the University of Minnesota have gained new insight into one of the most puzzling aspects of epilepsy treatment: why some epileptics fail to respond to anti-epileptic medications.

Using a rodent model of epilepsy, the research team found one of the body's own neurotransmitters released during seizures, glutamate, turns on a signaling pathway in the brain that increases production of a protein that could reduce medication entry into the brain. This may explain why approximately 30 percent of patients with epilepsy do not respond to anti-epileptic medications, says Dr. David Miller, a principal investigator in the NIEHS Laboratory of Pharmacology and a co-author of the study, which appears online and was published in the journal Molecular Pharmacology.

The two-year study was conducted by researchers at the NIEHS, part of the NIH, and the University of Minnesota College of Pharmacy and Medical School, in collaboration with Heidrun Potschka's laboratory at Ludwig-Maximilians-University in Munich, Germany.

"Epilepsy poses unique problems because patients are taking drugs throughout their lifetime, but as the disease progresses, they become resistant to certain drugs, which makes it really difficult for physicians to help them," Miller says.

The researchers identified the mechanism by which seizures increase production of a drug transport protein in the blood-brain barrier (BBB), known as P-glycoprotein, and suggest new therapeutic targets that could reduce resistance. The 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 administered anti-epileptic drugs into the brain in some patients.

P-glycoprotein forms a functional barrier in the BBB that protects the brain by limiting access of foreign chemicals. Increased levels of P-glycoprotein in the BBB has been suggested as one probable cause of drug resistance in epilepsy, Miller explains.

Using isolated brain capillaries from mice and rats and an animal model of epilepsy, the researchers found that glutamate, a neurotransmitter released when neurons fire during seizures, turns on a signaling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein in these experiments. Increased transporter expression was abolished in COX-2 knockout mice or by COX-2 inhibitors.

Targeting blood-brain barrier signals that increase P-glycoprotein expression rather than the transporter itself suggests a promising way to improve the effectiveness of anti-epileptic drugs, but because these findings provide insight into only one mechanism that underlies drug resistance in epilepsy, more research is needed before new therapies can be developed, Miller says. Miller points out that 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. Researchers plan to conduct further animal experiments in a population of drug-resistant epileptic rats, he adds.

"There seems to be a simple relationship between this transporter and drug resistance in epilepsy, but with many of the drugs, it is still not clear whether we have the right mechanism, although we may have the right target," Miller says.

"There is no consensus in the field as to how this transporter and drug resistance are related, but we do know that if you inhibit the transporter, you knock down drug resistance," he adds. "Sometimes, all of biology doesn't work out right. There are some holes we don't understand, but that is what keeps us going."

Amy Swinderman

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