Scientists have discovered in a study on mice how a neurotransmitter that the body releases during epilepsy seizures, known as glutamate, leads to an increased production of a protein that may reduce medication entry into the brain.
The finding attains significance as it may help discern why about 30 per cent of patients with epilepsy do not respond to anti-epileptic medications.
"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 Dr. David Miller, a principal investigator in the Laboratory of Pharmacology at the National Institute of Environmental Health Sciences (NIEHS).
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 anti-epileptic drugs into the brain.
In their study report, available in the online edition of Molecular Pharmacology, the researchers write that 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.
The researcher writes in the study report that increased levels of P-glycoprotein in the BBB has been suggested as one probable cause of drug resistance in epilepsy.
The researcher studied isolated brain capillaries from mice and rats and an animal model of epilepsy during the study.
They observed that glutamate turns on a signalling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein.
When COX-2 was knocked out in mice, the increased expression of P-glycoprotein was abolished.
The researchers, however, insist 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.
"These findings provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders," said Dr. Bjoern Bauer, 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," Bauer added.