Study finds zebrafish model may help identify treatments for a severe form of childhood epilepsy. Results of a study in “Nature Communications” suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.
Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. laboratory in 2005.
The researchers found that the zebrafish that were engineered to have a gene mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish.
“We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,” said Dr. Baraban. “Antiepileptic drugs shown to have some benefits in patients 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.”
In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures.
“The mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application,” said Dr. Baraban. “Using zebrafish 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.”
In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. “This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects,” said Dr. Baraban.
These findings suggest that mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy.
Dr. Baraban also noted that someday these experiments can be “personalized,” by looking at mutated zebrafish that use genetic information from individual patients.
Dr. Fureman noted that these findings not only describe a novel model of Dravet syndrome, but the positive results with an unexpected FDA-approved drug may lead to new therapeutic avenues. “There is more work to be done, but I am very pleased to see these initial results.For more information about Dravet syndrome and epilepsy, please visit:
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