Catherine Woolley, Northwestern University
Listen Now Download as mp3 from the show eLife episode 29: Microbiome mind control, epilepsy and parastic worms
About 1% of adults in countries like the UK have epilepsy. This is a neurological condition that occurs when groups of nerve cells adopt abnormal patterns of electrical activity that then become generalised across the brain causing the sufferer to lose consciousness. Usually the seizure is self-limiting and after a short time the brain resets itself to a normal neuronal firing pattern and the patient recovers. But sometimes a life-threatening condition called “status epilepticus” takes hold and the fit persists. Why wasn’t known. But now Catherine Woolley has found that the hormone oestrogen might be to blame, as she explained to Chris Smith…
Catherine - We tested two new ideas. First is that seizures stimulate the synthesis or production of oestrogens in the brain and the second is that oestrogen synthesis in the brain during a seizure fuels that seizure, making it worse. If this were true, that would give us a novel handle that we could use to control that seizure activity.
Chris - Is this oestrogen which is coming from say, the ovaries in a female or is this oestrogen being made elsewhere in the body?
Catherine - This is not oestrogen coming from the ovaries. This is actually oestrogen that is synthesised directly within the brain.
Chris - What do we think those oestrogen molecules made in the brain do?
Catherine - It’s actually been a longstanding question – what neurosteroid oestrogens might be doing in the brain. There has been until now, only circumstantial evidence that neurosteroid oestrogens actually are synthesised in the brain. And now we know that seizures are one of the circumstances in which they're synthesised and one of the roles that they play is to promote neural activity during that seizure. So, our hypothesis was that seizures initially stimulate oestrogen synthesis in the brain and that that sets up a feed forward loop that we then might be able to break by inhibiting the synthesis of oestrogens.
Chris - And so, that would be in keeping with this condition that’s called status epilepticus where you see an individual who has a fit but then they keep fitting. The seizure does not extinguish itself.
Catherine - That’s right. So status epilepticus is a condition that is considered to be a neurological emergency. It happens when a person has a prolonged episode of seizure activity that lasts for 5 minutes or longer, or when seizures occur in such quick succession that the person isn't able to regain consciousness between them.
Chris - So, how did you actually explore this? What did you do to try to find out whether it is down to oestrogen doing this?
Catherine - One experiment was to measure oestrogen levels in the brain before and during seizure activity using a technique called microdialysis and we found that when animals are having seizures, oestrogen levels increase in a part of the brain called the hippocampus which was very commonly involved in seizure activity.
Chris - So, that would fit in the first instance, if you excuse the pun, we’ve got a situation where in the context of seizure activity, levels of oestrogen go up. Does that prove that the oestrogen is causing the seizures to be maintained or merely that it’s a bystander effect?
Catherine - That alone does not prove any causal relationship between the neurosteroid oestrogen synthesis and seizure activity. To investigate that question, we used a drug called an aromatase inhibitor that blocks the synthesis of oestrogens. We gave that aromatase inhibitor just at the beginning of a seizure and found that inhibiting oestrogen synthesis dramatically weakened seizures, made them much less severe. This drug was effective either if we gave it directly into the brain or if we gave it IV that is inhibiting oestrogen synthesis throughout the body.
Chris - Might it not be though that that molecule, as well as inhibiting the production of oestrogen happens to naturally be an anticonvulsant drug and it just stops the seizure for some other reason, nothing to do with oestrogen?
Catherine - One way that a person can assess whether a drug is working through the mechanism that one anticipates is to use two different drugs with different chemical structures they have in common but they do the same thing. In this case, inhibit the aromatase enzyme and we did find that two different aromatase inhibitors had the same effect of suppressing seizure activity.
Chris - Therefore, would this suggest that this could be quite a useful mechanism in the clinic if we can administer agents like this or exploit this mechanism to get better control of patients who have poorly controlled epilepsy?
Catherine - That’s my hope. Aromatase inhibitors are clinically used now. In fact, we used one that is used now to treat breast cancer. And so, aromatase inhibitors are generally safe to use and I'm optimistic that aromatase inhibitors might indeed be a way to control neural activity during a seizure in a way that is targeted more toward the seizure activity than current anti-seizure medications are targeted.