A new study from Northwestern University has found that aromatase inhibitors, a class of drug that inhibits estrogen production and is used to treat breast cancer, has been found to suppress dangerous brain seizures rapidly and effectively.
The research suggests a new approach to treating seizures in humans, shutting down the brain’s production of estrogen when a seizure first begins.
Current seizure treatments are not targeted, working by dampening neural activity generally. They produce many side effects, such as drowsiness, dizziness or difficulty concentrating. id Catherine S. Woolley, senior author of the study, said:
“The effect was profound and very clear. This shows that clinically available drugs could be effective therapies for suppressing seizures in humans."
The research was conducted in a rat model of status epilepticus, a condition characterized by a prolonged episode of seizure activity. To their surprise, Woolley and postdoctoral fellow Satoru M. Sato also discovered that seizures stimulate the production of estrogens in the brain of both males and females and that this plays a previously unknown role in the escalation of seizure activity.
Estrogen synthesis during a seizure fuels the seizure, making it worse.
“Status epilepticus is a neurological emergency,” Woolley said. “This occurs when large groups of connected neurons fire excessively and in synchrony for a prolonged time. Recognizing that estrogen synthesis during seizures fuels seizure activity gives researchers a specific target for therapeutically breaking the dangerous escalation cycle."
The study builds on past work showing estrogen increases neuronal activity through a number of mechanisms.
[caption id=“attachment_79327” align=“aligncenter” width=“640”] Researchers found seizure activity is strongly suppressed in the animal that received the aromatase inhibitor just after seizure onset (bottom two signals), whereas seizure activity continues in the control animal (top two signals). Yellow is an EEG recording, and blue is a way of quantifying power in the EEG recording. Credit: Northwestern University[/caption]
The scientists injected some male and female animals with an inert substance and some with an aromatase inhibitor, either letrozole or fadrozole, just after the start of a chemically induced seizure.
An aromatase inhibitor inhibits estrogen synthesis; letrozole, or Femera®, is used clinically to treat breast cancer in postmenopausal women. They studied the animals for up to six hours and found both fadrozole and letrozole strongly suppressed seizures in both sexes.
Seizures vs. Epilepsy
In another part of their study, Woolley and Sato found the impact of seizures on estrogen production in the hippocampus was surprisingly large in both sexes, showing a two- to three-fold increase during seizures.
Woolley said it is important to distinguish between seizures and epilepsy, which are not synonymous. Epilepsy, which affects about 1 percent of the population, is a condition in which a person has spontaneous recurrent seizures, often lasting only a few minutes.
Status epilepticus is a more severe seizure episode, affecting about 40 people per 100,000 per year.
Overall mortality rates for status epilepticus is estimated at 20 percent, and patients who recover have an increased likelihood of subsequent unprovoked seizures, the researchers say. New approaches to acute seizure control are needed.
Satoru M Sato, Catherine S Woolley Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model eLife 2016;5:e12917