The underlying cause of 10% to 20% of epilepsy cases is a head injury. A new drug has been found to be effective in preventing this tragic outcome and may minimize the brain damage caused by seizures in patients who have already been diagnosed with epilepsy.
A group of researchers from the Ben-Gurion University of the Negev, the University of California, Berkeley in the USA, and the Medical University, Sarita, in Berlin report, in an article published in the current issue of the prestigious journal Annals of Neurology, that a drug for the treatment of hypertension, which is in widespread clinical use, is effective in preventing maximum The cases of post-traumatic epilepsy, in the model of the disease in rodents. If a study now being carried out independently confirms the results, it will be possible to start clinical trials in humans in the coming years.
"This innovative approach, according to which we prevent the development of epilepsy, is different from the treatment with existing drugs, whose purpose is to prevent seizures only after the development of the disease," says Alon Friedman, professor of physiology and neurobiology and a member of the Zalotovsky Center for Neuroscience at Ben-Gurion University of the Negev. "These drugs have little success and many side effects, so we are very excited about the new approach."
The group, led by Alon Friedman, Daniela Kaufer, a professor of integrative biology and a member of the Helen Wills Institute for Brain Research at the University of Berkeley, and Eva Heinemann, a professor at the Medical University of Berlin, provide for the first time an explanation of how epilepsy develops after a head injury, stroke or encephalitis: their joint research, which was published on For about a decade, there is evidence of a functional impairment of the blood-brain barrier - a complicated mechanism made up of different types of cells, which surrounds the blood vessels in the brain - resulting from brain trauma.
"The current study offers, for the first time, a specific mechanism underlying the development of epilepsy in patients who have experienced brain trauma or as a result of dysfunction of the blood-brain barrier, and its possible prevention using a drug approved for use by the American Food and Drug Administration (FDA)," says Prof. Cowper.
Use of the drug losartan (trade name Kozar) prevented epileptic seizures in 60% of the experimental animals, while 100% of the untreated animals suffered from seizures. In addition, among the 40% of treated animals that were diagnosed as epileptic, the number of seizures was about a quarter of that of animals that were not treated with the drug. The experiment showed that a short-term treatment of three weeks after the brain injury was enough to prevent most cases of epilepsy for a period of months.
"These are very exciting results, which show us that the drug did indeed prevent the development of the disease and not just reduce its symptoms," says Friedman.
The collapse of the blood-brain barrier
Friedman and Cowper have been collaborating in the study of brain injury outcomes for about two decades. The center of Friedman's research interest is the blood-brain barrier, which in a normal state protects the brain from potentially harmful substances or bacteria in the blood and also prevents substances in the brain from leaking into the bloodstream. Together, the researchers previously showed that the collapse of the barrier causes inflammatory processes and the development of epilepsy. They isolated the effect of a single protein, known as albumin, which is the most common protein in the blood.
In 2009 they showed that albumin acts on astrocytes, brain support cells, by binding to the transforming growth factor beta (TGF-beta) receptor. This response triggers a multi-step system, leading to local inflammation that permanently damages brain connectivity, resulting in abnormal neuronal firing, which characterizes epilepsy. The current publication demonstrates that blocking the activity of the receptor with losartan stops this multi-step system and prevents the development of the disease.
The importance of the absence of side effects
Guy Bar-Klein, a doctoral student at Ben-Gurion University and a research partner, looked at a long list of drugs before discovering that losartan (which is approved for the treatment of hypertension because it is an angiotensin II receptor blocker was also found to inhibit the activity of the transforming growth factor beta receptor. The treatment It was found to be effective when given in the drinking water of the rodents, a result that indicates the leakage of the drug into the brain through the blood-brain barrier, apparently due to the damage to it.
Friedman's research group in collaboration with Dr. Shelf from the Soroka Medical Center developed a protocol for diagnosing the function of the blood-brain barrier, whether normal or damaged, using magnetic resonance imaging (MRI). This method will allow doctors to treat losartan as a preventive measure in patients diagnosed with increased blood-brain barrier permeability. Friedman says that the barrier may remain open for only a few weeks after the injury, so there is no need for long-term treatment to prevent the damage.
"In the current situation, when a patient is rushed to the emergency room after brain trauma, the risk that he will develop epilepsy is 10% to 50%. These patients also tend not to respond to the drugs available to treat epilepsy." Prof. Friedman says. "Also, since damage to the blood-brain barrier also causes other complications in patients, including intracerebral hemorrhages and other functional disorders, I am hopeful that our research will help prevent additional complications that patients suffer from."
This research was supported by the Seventh Program of the European Union, the Israel Science Foundation, the US-Israel Binational Science Foundation, and the National Institute of Neurological Disorders and Stroke of the US National Institutes of Medicine (RO1/NINDS NS066005).
Louisa P. also took part in the study. Casho, a former doctoral student at UC Berkeley and now a postdoctoral researcher at the Center for Memory and Learning at the University of Texas, graduate students Lynn Kaminecki, Ofer Perger and Iti Weisberg from Ben-Gurion University of the Negev, researchers Eva Hinman and Karl Schuknecht from the Medical University of Berlin, Germany, Paul Chang , a graduate student at UC Berkeley and postdoctoral researchers Su Young Kim and Lydia Wood of the Helen Wills Brain Institute at UC Berkeley.
More info:
• Losartan prevents acquired epilepsy via TGF-β signaling suppression (Annals of Neurology, 2014)
Seizing Control of Brain Seizures (2014)
• Drugs may prevent epilepsy & seizures after brain injury (2009)
For more information, you can contact:
Prof. Alon Friedman - alonf@bgu.ac.il, 8-647-9884 / 8790
Prof. Daniela Cowper – danielak@berkeley.edu, 1-510-642-9346
Here is a link to the article:
http://onlinelibrary.wiley.com/doi/10.1002/ana.24147/abstract
And a link to an article on the website of the International Association for the Prevention of Epilepsy:
http://www.ilae.org/Visitors/News/basic-science-of-epilepsy.cfm
Caption for the photo:
Prof. Alon Friedman.
Link to image:
http://imagelibrary.bgu.ac.il/pf.tlx/hshL1h_2B0y3
Photo: Danny Machlis, Ben-Gurion University
Caption for the photo:
Guy Bar-Klein.
Link to image:
http://imagelibrary.bgu.ac.il/pf.tlx/Iw3IZZIOHzVO
Photo: PR.
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