September 3, 2013
Researchers Use Zebrafish To Reel In New Epilepsy Treatment
Brett Smith for redOrbit.com - Your Universe Online
The phrase ‘thinking outside the box’ has become so common these days, it’s almost thought of as an oxymoronic cliché. However, a group of University of California, San Francisco researchers, doing just that, may have stumbled onto a new drug to treat a certain form of childhood epilepsy.
Although previous studies have found antihistamines can make seizures worse, the UCSF researchers found that the antihistamine clemizole can prevent seizures in zebrafish modified to replicate the rare form of childhood epilepsy called Dravet Syndrome.
"This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects," said study author Scott C. Baraban, a neurologist at UCSF.
Instead of expanding on previous drug research, Baraban and colleagues used a random test of 320 compounds that had already been approved for use by the Food and Drug Administration. The team said they could not tell which drugs were causing the observed results until after the individual tests had been completed.
In discussing the surprising beneficial effect of clemizole, the researchers said they had tried ten other antihistamines, including four tested in the study, and none showed an ability to block seizures. Baraban said that the antihistamine itself was most likely not the reason behind the drug’s anti-seizure effect. He added that the group will be performing studies to try to figure out the actual mechanism.
Zebrafish used in the study were engineered to have a single mutation in the SCN1A gene that causes Dravet Syndrome. The fish were found to exhibit some of the same characteristics, including spontaneous seizures, typically seen in children with the condition, but not seen in normal, healthy zebrafish.
"We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients," Baraban said. "Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish."
To reach their findings, which were published in the journal Nature Communications, the researchers also developed a quick automated drug screen to test the efficacy of various compounds in their modified zebrafish. By tracking behavior and brain activity in the fish, the team was able to determine if the compounds had an impact on seizures.
"SCN1A mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application," Baraban said. "Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures."
The research was funded by the Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) program at the National Institutes of Health. The program supports unique approaches to research with an eye on the potential for big results for biomedical science.
"The goal of the EUREKA program is to provide a means to test high-risk ideas to see if they are worth pursuing further. These kinds of ideas often come from left field and are very creative. Since they are so unique, however, there may not be any existing preliminary data to support the hypothesis or demonstrate feasibility. EUREKA grants provide an opportunity to gather this information," said Brandy Fureman, program director at the National Institute of Neurological Disorders and Stroke.