Scientists from Ben-Gurion University, University of California, Berkeley, and Charité-University Medicine in Germany found that losartan (marketed under the brand name Cozaar), a common blood pressure medication, significantly cut down seizures in rats that suffered head trauma due to injuries, according to a study published in the current issue of the Annals of Neurology.
“This is the first-ever approach in which epilepsy development is stopped, as opposed to common drugs that try to prevent seizures once epilepsy develops,” said Alon Friedman, professor of physiology and neurobiology and a member of the Zlotowski Center for Neuroscience at BGU. “Those drugs are administered for many years, have a limited success and involve many side effects, so we are excited about the new approach.”
The research shows not only how the drug helps alleviate epileptic attacks, but, for what is said to be the first time, how brain injury caused by a blow to the head, stroke or infection leads to epilepsy. The cause is in a breach of the blood-brain barrier (BBB), the tight wall of cells lining blood vessels in the brain that protects brain cells from the infectious bacteria carried in the bloodstream, the researchers said.
That breakdown can allow a protein called albumin, the most common protein in blood serum, to cross the barrier. Albumin is a major factor in the development of epilepsy, Friedman and Daniela Kaufer, a UC Berkeley researcher, showed in 2009.
The two investigated the role of albumin in epilepsy for over a decade. Based on the research, the team of researchers led by the two have concluded that albumin affects astrocytes, the brain’s support cells, by binding to the TGF-β (transforming growth factor-beta) receptor. This initiates a cascade of steps that lead to localized inflammation, which appears to permanently alter the brain’s wiring, leading to the electrical misfiring characteristic of epilepsy, Friedman said.
The team, along with Guy Bar-Klein, a doctoral student at Ben-Gurion University who co-wrote the study, tried several drugs before discovering losartan, which is approved to treat high blood pressure because it blocks the angiotensin II receptor 1, but has the side effect of blocking TGF-β signaling. In tests, losratan prevented seizures in 60 percent of the rats tested; rat control groups that were hit on the head in the manner studied by researchers developed seizures 100% of the time. For the 40% of rats that did develop seizures while taking the drug, the attacks averaged about one quarter the number typical for untreated rats. The test showed that administering losartan for three weeks at the time of injury was enough to prevent most cases of epilepsy in normal lab rats in the following months.
“Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50% chance of developing epilepsy, and epilepsy from brain injuries tends to be unresponsive to drugs in many patients.” Friedman said. What is really exciting, Kaufer said, was the fact that this treatment could be applied on a wide basis immediately. “This study for the first time offers a new mechanism and an existing, FDA-approved drug to potentially prevent epilepsy in patients after brain injuries and once they develop an abnormal blood-brain barrier.”
“This is a very exciting result, telling us that the drug worked to prevent the development of epilepsy and not by suppressing the symptoms,” Friedman said. “Since breakdown of the blood-brain barrier may also be associated with other complications, including bleeding and changes in cognitive functions, we are expecting that our approach will prevent complications other than epilepsy.”