TGF beta blocker prevents epilepsy following traumatic brain injury

Dr. Alon Friedman, a neurosurgeon, professor and researcher at Ben-Gurion University of the Negev, working with researchers from UC Berkeley, California have identified a TGF Beta Blocker that when given to rats prevents epilepsy after brain damage, according to a new study appearing in the July 15 issue of the Journal of Neuroscience.

The researchers found that they could prevent the brain changes leading to epilepsy in rats by treating the animals with a drug that blocks transforming growth factor-beta receptor (TGF-beta). Providing these drugs, they found that the hyper-excitability that is normally present after a brain trauma could be blocked. The blockers also prevent a majority of the gene expression changes that they identified following brain injury.

"The idea is to identify and treat only the brain injury patients that are at risk for developing epilepsy, using novel imaging approaches that we are currently developing. At least in the rats, it works now," Friedman says.

"If the findings are confirmed in humans, a TGF-beta blocker may prevent many cases of epilepsy in accident victims, including soldiers or civilians who suffer brain trauma from bombing," Friedman explains.

"Because of better medical care, many victims now survive severe traumatic brain injuries. Those with severe head injuries are thought to have a 25 to 50 percent chance of eventually developing epileptic seizures, yet no treatment exists to prevent the development of epilepsy. Once it develops, drugs are the only option, and even those fail to control seizures in 30 percent of cases."

The results are the culmination of more than 14 years of research, exploring the hypothesis that brain injury-induced epilepsy is caused by leakage of blood components into the brain through the damaged "blood-brain barrier", whether caused by trauma, brain tumors, infection, meningitis, or hemorrhagic or ischemic stroke.

The idea originated with neurosurgeon Alon Friedman, who at the time was a physician in the Israeli army, and now is one of the leading scientists at BGU's Brain Imaging Research Center.

"While observing patients, we hypothesized that breech of the blood-brain barrier - a sheath of tightly joined cells that lines the capillaries in the brain to prevent intrusion of bacteria and potentially dangerous blood-borne molecules - somehow triggers events that damage brain cells. In 2004 we published the first direct evidence in animal experiments, showing that opening the blood-brain barrier and the diffusion of blood components into the brain results in the development of epilepsy."

Friedman teamed up with Daniela Kaufer, then a graduate student at The Hebrew University, on a series of experiments that has gradually provided support for the hypothesis and convinced many that this is a totally new and valuable way of looking at epilepsy. Now an assistant professor of integrative biology at the University of California, Berkeley, she has teamed with Friedman and other colleagues to systematically sift through the components of the blood and, in 2007, reported that the major culprit in epileptogenesis seemed to be albumin, the main protein in blood serum.

This research won Friedman the prestigious Michael's Prize for epilepsy research, and a highly competitive award from CURE (Citizens United for Research in Epilepsy) was granted to both Friedman and Kaufer in 2008.

In the current experiments performed by Yaron David, a graduate student at BGU, and Luisa Cacheaux, a graduate student from UCB, the researchers used serum albumin to trigger epileptogenesis in rats' brains and showed that albumin binds to TGF-beta receptors and triggers the expression of a myriad of genes that are also turned on when the blood-brain barrier is breeched by other means. The genes expressed involve not only the normal TGF-beta pathway, but also genes involved in inflammation and in reducing inhibition of neurons.

The actual damage is thought to be caused by uninhibited firing of neurons, so called hyper-excitability, that can exhaust and kill the neurons, altering the nerve network in the brain and leading to reorganization of neurons to create short-circuits that precipitate seizures.

"Epilepsy is neurons firing together in synchrony, which leads to a storm of electricity," Kaufer said. "The brain by itself has mechanisms to inhibit the release of inhibitory signals through an inhibitory neurotransmitter that is supposed to shut down the firing. In epilepsy, you don't get shutdown of firing and it spirals out of control."

The team triggered the same processes by introducing TGF-beta into the brain, and were able to block these molecular and functional changes with drugs that block activation of the TGF-beta pathway.

Kaufer noted that TGF-beta blockers might also prevent further damage in those with persistent seizures - a condition known as status epilepticus - because these non-stop seizures also open the blood-brain barrier.

Friedman continues to monitor treated rats with an electroencephalograph (EEG) to see what percentage of the rats goes on to develop epileptic seizures. Together with BGU's Dr. Moni Benifla, an epilepsy surgeon, and Dr. Ilan Shelef, a neuroradiologist, they are working on ways to detect blood-brain barrier leakage in patients following brain injuries and follow the potential development of epilepsy in these patients at Soroka University Medical Center. Kaufer and her lab colleagues continue to explore the role of blood-brain barrier breech in epilepsy, and the impact of stress on the brain.

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