Mutant Zebrafish and Antihistamines Hold Hope for Severe Epilepsy Treatment

An antihistamine discovered in the 1950s and a mutant zebrafish potentially hold the key to a treatment for a severe form of epilepsy.

Dravet syndrome is a rare genetic disorder that begins in early childhood. It often has lifelong, disabling consequences, including dozens if not hundreds of seizures in an individual every day.

Researchers at the University of California San Francisco (UCSF) believe their find may also be used to find drugs for all forms of epilepsy.

Scott Baraban, lead author of the article published online in Nature Communications, explained that zebrafish were increasingly being used in place of rodents to screen drugs for rare genetic disorders.

However, they had not been used for epilepsy until the team found that a zebrafish with the same genetic mutation as the one that causes Dravet syndrome.

The disorder develops because of mutations in the Scn1a gene, which is involved in regulating how charged ions to pass through the membranes of neurons. In Dravet syndrome, these channels let in too many ions and the neurons "over-fire", causing seizures.

Unlike some forms of epilepsy that can be targeted and treated surgically by removing malfunctioning brain tissue, genetic forms of the disease cannot because they involve neurons throughout the organ.

By accident, the team discovered that the antihistamine drug clemizole was effective in inhibiting seizure activity in zebrafish with the genetic mutation.

Completely unexpected

They made their discovery by testing various compounds on the fish and tracking their behaviour. They tested 320 compounds approved by the Food and Drug Administration to see what worked, but did not look to see what the compound was until the test was over.

Antihistamines can make seizures worse so it is unlikely the team would have focused on it as a possible treatment.

"This finding was completely unexpected. Based on what is known about clemizole, we did not predict that it would have antiepileptic effects," Baraban said.

Why clemizole works is unknown, but the group tested 10 other antihistamines and none blocked seizures in the same way. They plan to investigate why the drug is effective in preventing seizures.

Baraban also said their method of testing drugs is highly effective and can be used to screen drugs for any form of epilepsy caused by mutations in a single gene.

"Scn1a mutants seize often, so it is relatively easy to monitor their seizure behaviour 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 behaviour. 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."