|Brain Study May Lead to Improved Epilepsy Treatments
Using a rodent model of epilepsy, researchers 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.
Researchers say this may explain why approximately 30 percent of
patients with epilepsy do not respond to antiepileptic medications.
The study, conducted by researchers at the National Institute of
Environmental Health Sciences (NIEHS), part of the National Institutes
of Health, 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, is available
online and will appear in the May 2008, issue of Molecular
"Our work identifies the mechanism by which 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., a principal
investigator in the NIEHS Laboratory of Pharmacology and co-author
on the paper.
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 administered antiepileptic drugs into the brain.
Miller explained that P-glycoprotein forms a functional barrier
in the BBB that protects the brain by limiting access of foreign
"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 has been suggested
as one probable cause of drug resistance in epilepsy.
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.
It has yet to be shown in animals or patients that targeting COX-2
will reduce seizure frequency or increase the effectiveness of
"These findings provide insight into one mechanism that underlies
drug resistance in epilepsy and possibly other central nervous
system disorders," said Bjoern Bauer, Ph.D., lead author on the
publication. "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 primary mission of the National Institute of Environmental
Health Sciences (http://www.niehs.nih.gov/)
(NIEHS), one of 27 Institutes and Centers at the National Institutes
of Health, is to reduce the burden of human illness and disability
by understanding how the environment influences the development
and progression of human disease. For additional information, visit
the NIEHS Web site at http://www.niehs.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Bauer B, Hartz AM, Pekcec A, Toellner K, Miller DS, Potschka H. Seizure-Induced
Upregulation of P-glycoprotein at the Blood-Brain Barrier through
Glutamate and COX-2 Signaling. Molecular Pharmacology. 2007
Dec 19 [Epub ahead of print] doi:10.1124/mol.107.041210.