Seizures in Dravet Patients May Be Associated with Abnormal Serotonin System, Preclinical Study Suggests
These results shed light on the potential of serotonin-boosting therapies, such as Fintepla (ZX008), to reduce seizures in Dravet patients.
The study, “Serotonin Abnormalities in Dravet Syndrome Mice Before and After the Age of Seizure Onset,” was published in the journal Brain Research.
Dravet syndrome is a severe type of epilepsy that usually manifests during the first year of life and is characterized by seizures, motor difficulties, cognitive deficits, and increased mortality.
Premature death occurs in 21% of Dravet patients, with sudden unexpected death in epilepsy — which occurs during or immediately after a seizure — accounting for nearly half of these deaths.
Serotonin is a key chemical messenger molecule that allows communication between nerve cells, playing a role in several psychological, emotional, motor, and cognitive responses.
Numerous studies have highlighted an association between serotonin levels and activation of serotonin receptors at the onset of seizures, with increased serotonin levels and receptor activation showing a protective effect against seizures.
Moreover, a previous study in a zebrafish model relevant to Dravet syndrome showed that the activation of two serotonin receptors — 5-HT2A and 5-HT2C (5-HT2A/2C) — in these fish eased their motor and epileptic-related symptoms.
These findings suggested that activating serotonin receptors could have positive therapeutic effects in Dravet patients.
Fintepla (ZX008), a low-dose oral solution of fenfluramine hydrochloride, is being developed by Zogenix as an investigational therapy for the treatment of epileptic seizures linked to Dravet syndrome. Its anti-epileptic properties are associated with the stimulation of serotonin release in the brain.
Results of three Phase 3 clinical trials — ZX008-1501 (NCT02682927), ZX008-1502 (NCT02826863), and the open-label extension study (NCT02823145) — have so far shown that Fintepla improves behavioral, emotional, and cognitive control and reduces seizure frequency in children and young adults with Dravet syndrome.
However, the potential changes in the serotonin system in Dravet patients, which may help explain the observed therapeutic effects of serotonin-boosting therapies such as Fintepla, remain poorly understood.
Therefore, researchers at Boston Children’s Hospital and Harvard Medical School set out to evaluate the serotonin system in a mouse model of Dravet syndrome at several timepoints, including before and after seizure onset (at 19 days of age).
They specifically assessed the serotonin levels and function of three serotonin receptors — 5-HT1A and 5-HT2A/2C — in the brain of these mice.
Before seizure onset, Dravet mice had reduced serotonin levels in the median and dorsal raphe nuclei — the main location of serotonin production in the brain — and a reduced function of 5-HT1A serotonin receptors, compared with healthy mice. These features suggest that the mice were more vulnerable to seizures.
After the development of seizures, while their serotonin levels were comparable to those found in healthy mice, Dravet mice had an increased function of all three receptors.
These findings indicated that the sensitivity of serotonin receptors to serotonin in mice with Dravet syndrome reversed with age, with an early insensitivity converting into hypersensitivity in adulthood.
According to the researchers, these changes in serotonin receptor sensitivity “may be an adaptive change because activation of these receptors should be protective against seizure.”
The researchers noted that the positive effects of serotonin-boosting therapies, such as Fintepla, may therefore be associated with the hypersensitivity of serotonin receptors in Dravet patients.
They also hypothesized that mice with low serotonin as well as reduced 5-HT1A receptor function could be particularly vulnerable to early death, which could explain why Dravet mice who survived had serotonin levels comparable to healthy mice later in life.
“These and possibly other developmental changes in the serotonin system could relate both to the age of onset of seizures as well as the transient age-dependent vulnerability to early death,” the researchers wrote.
Future studies focusing on the underlying mechanisms of these changes in the serotonin system may help understand the age-dependent responses in this mouse model and develop new therapeutic strategies for people with Dravet syndrome, they said.