Epilepsy - Preventing Seizures After Traumatic Brain Injury - Tobias Engel, RCSI & FutureNeuro, Ireland
Tobias Engel talks about potentially preventing seizures and epilepsy caused by Traumatic Brain Injury (TBI)! He discusses his study into the P2X7 receptor's role in TBI and its potential to reduce inflammation, seizures, epilepsy, neurodegeneration, and mood disorders. Tobias also speaks of the potential for improved quality of life for those with TBI-related epilepsy in the future. Transcription and links the video, podcast, and more about Tobias below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Tobias Engel
“I do think, maybe, there's potential that it not only suppresses seizures but hopefully that the effects are not restricted only to seizure activity but other things, hopefullyl, as well.”
00:10 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and, welcome to, or welcome back to: Epilepsy Sparks Insights. If you’re new and you haven’t done so already, please like and comment on this episode and subscribe to our channel - so to support our mission - which is to decrease the discrimination faced by and improve the quality of life of those affected by the epilepsies…. Aaaaand get everyone appreciating the amazing, exciting epilepsy research thatis out there!
So, today we are going to be hearing about research into preventing epilespy onset after Traumatic Brain Injury. In fact, our guest, neuroscientist Tobias Engel will share his research into the plasma membrane receptor P2X7 - showing how to potentially, not only avoid seizure onset and epilepsy, but also even prevent the mood changes and mental health disorders that commonly result!
01:01 Tobias Engel
I did my undergraduate studies in Germany, then I went to Spain. This was all in biology. And then I moved on to… I was actually in Madrid, where I did my PhD, and this was on neuroscience. And at the time I was working there in Alzheimer's Disease. So, this I finished in 2005/6-ish - I can't remember now(!) - and then I moved to Ireland where I started working in epilepsy as a postdoc. And then 5years later, 10 years ago, more or less, I established my own research lab over there in Ireland, in Dublin. And here I'm based at the Royal College of Surgeons in Ireland.
01:37 Torie Robinson
Your recent paper which has been out on… I mean, [I’m] just simplifying it here but basically: post-traumatic injury induced epilepsy and then a P2X7 antagonist!
01:48 Tobias Engel
Okay, So, maybe I start with, you know, what we're working [on] and the main focus in our lab.
01:53 Torie Robinson
Mm-hmm.
01:53 Tobias Engel
So, what we're working [on] in our lab, we're trying to identify new ways how to prevent epileptic seizures, how to treat epilepsy. And we're trying to look at things which are not common to commonly used anti-seizure medications. Because we do have, you know, there's people who don't respond to treatments. So, what we try to do is to find alternative pathways to block these. So, here the main focus, I guess, is when they're looking at inflammation. So, we know that in people with injuries to the brain, also, in epilepsy, you have this increase in inflammation, chronic inflammation in the brain. So, what we're trying to do is here, what has been shown before is that this inflammation can actually contribute to people having seizures. They can start seizures, but it can also, make it worse, the seizures over time (so, the disease can progress even more). So, what we're trying to do is find different pathways we can block with drugs if possible, and then this will, you know, block this or stop this inflammation in the brain and thereby hopefully also, reducing seizures. Okay.
02:57 Torie Robinson
And just to clarify, So, this… what you're looking into, are you thinking of something that would be used after a traumatic brain injury to prevent seizure and epilepsy onset?
03:09 Tobias Engel
Yes, this is the idea. So, really, the idea is not only to suppress seizures, but what we're really looking for is things which will suppress, well, which stop seizures, but will eventually modify the course of the disease. So, in the case of traumatic brain injury (I can come to this later), so then this is idea is here that after an injury that you can actually prevent it from happening, So, you don't need your medication later on. And this is also, really, I think, most of the labs is now really the research focus rather than just suppressing seizures is actually, you know, stop it from happening or stopping it at all (epilepsy).
03:44 Torie Robinson
I can reassure you that that's what most people would prefer(!), so... haha.
03:48 Tobias Engel
Exactly.
03:50 Tobias Engel
So, the study what we just published is… this was a study where we looked at the signalling system, this P2X7 receptor in traumatic brain injury. And the reason why we chose the topic of traumatic brain injury is basically that we know that after traumatic brain injury, you have an increased inflammation in the brain, so, it makes sense to, you know, to block something which would eventually hopefully reduce this inflammation, so this is where our P2X7 receptor comes in. And there have been studies before - not on epilepsy - but, they've shown that when you block this receptor in animal models, that this can protect the brain from damage (which is one part of traumatic brain injury). And they've also, seen, because you do have other behaviour changes in animals, but of course also, in patients, you know? So, they've shown that this can also, have other effects that it can normalise this behaviour. So, the idea here was really building on this: what was there before, and seeing whether this also reduces epilepsy. I mean, just to mention here; we have used different models with the signalling system and that worked quite well in that we have this reduction in seizures and also, in epilepsy. So, now we wanted to see in traumatic brain injury. And the other part - before I forget - of course; traumatic brain injury is one of the leading causes of acquired epilepsy in adults. So, I guess it makes much sense to look for, you know, treatments for then.
05:08 Torie Robinson
You mentioned mood change as well - after traumatic brain injury. It's something that people don't really talk about much. So, this this potential drug could also, minimise impacts on mood. Is that right?
05:22 Tobias Engel
Yes. This P2X7 receptor because it induces inflammation. We know inflammation is involved in so many things in the brain, not only on seizures of course, but you have, yes, mood disorders, many… everything: depression, we know there can be an increased inflammation in the brain. It can also, contribute to this, you know, after TBI, for example; you have this new degeneration going on in the brain, which is ongoing, so it can also contribute to this. The idea of blocking this is not only reducing seizures, but also, other parts of the primary disease, which would be here the TBI.
05:59 Torie Robinson
Mm-hmm.
06:00 Tobias Engel
So, the study what we did here, we induced TBI in our models and our mice. And these mice then they will develop epilepsy just [like] in humans after a while (and in the mice it's then about 2 months, more or less, right). So, what we did then is: induced TBI, then we treated these mice a week later with our P2X7 antagonists, and then, later on we quantified the seizures what these mice got, [and] the seizure severity. And what we found here is what when we treated these mice just shortly after TBI for a week, we saw later on, really, that these seizures… the risk of seizures was reduced to a normal level - almost to control levels! So, first of all, they did work. And the second one… I think the nice one here is that you have these long-lasting effects. You know, then, because we're not only looking for seizure suppression, but we do look after this disease modification: can we modify the disease from developing?
06:52 Torie Robinson
Mm-hmm.
06:53 Tobias Engel
So, we found here that the risk of seizures was much lower than even like weeks after the treatment. So, hopefully… this is the aim of what we're trying to do, this disease modification. What we also looked at in our study was not only seizures, but then we looked also… because TBI you have neurodegeneration, so, we wanted to see does it have effects on neurodegeneration if…you know, you have this contusion volume, it's getting bigger, so when you look in the cortex you have less neurons. So we saw there was really also, nice protection - so there was less degeneration of neurons. And what we found as well when we did behaviour tests [was] that these mice then also, behaved better. So, for example, we looked at hyperactivity (and I think this is in TBI patients as well; what you see [is] that patients [are] hyperactive) -we saw (in the mice anyway) that this was reduced also, to normal levels. So, you know, the treatment does suppress seizures, but you have also, other benefits from it.
07:49 Torie Robinson
Amazing. And I'm just thinking in humans potentially, like, so, obviously, people with epilepsy, a much higher rate of psychiatric illness, as you know, imagine if we didn't have to take all these antidepressants or antipsychotics or whatever, in addition to not having to take the anti-seizure medications, that would be pretty amazing.
08:09 Tobias Engel
Yes it would! I mean, I’m not saying… I'm not saying… I sure whether this is going to be the wonder drug…
08:12 Torie Robinson
Of course we don't know but…
08:12 Tobias Engel
…probably not I would say. But I think, I do think, maybe there's potential that it not only suppresses seizures but hopefully that the effects are not restricted only to seizure activity but other things, hopefullyl, as well.
08:27 Torie Robinson
And do you just give the drug to… the treatment to the mice once? Or is it several times over a period of time?
08:33 Tobias Engel
So, this was during 1 week, once a day. But, I mean this was oral gavage, so we gave them, can just take the drug in the, you know, basically a food. So, this would be once a week. Yes, there was 1 week. But. I mean, this is one of the things we have to test as well: so, how long do you have to give it?
08:54 Torie Robinso
Of course, yeah.
08:54 Tobias Engel
We don't know whether the treatment window with once would be enough (a week), so, this is still things, of course, to figure out.
09:00 Torie Robinson
When would that be used? At what stage of a person's illness?
09:06 Tobias Engel
So, the antagonist (they would be the drugs targeting this receptor), I would think that this would usually be used when you have either seizures or acute pathology, or, for example, if I can, when we come back to the study, after a brain injury such as a TBI, when you have this increased inflammation and then you can use, I think, these antagonists, these drugs and this will dampen down then this inflammation.
09:29 Torie Robinson
Okay and do you foresee this potentially as something that could be used as on anybody who has traumatic brain injury to just prevent it… like, just to keep, you know, fingers crossed this doesn't happen or would it be potentially used in people who seem to be at higher risk of developing seizures?
09:47 Tobias Engel
That's also, a good question! So, for these antagonists, for this treatment to be useful, I think you do need this inflammation in the brain. This is where it works. Now, I think usually you will develop epilepsy, if I'm not wrong; when you have more severe traumatic brain injuries, so more at risk. And after this brain injury, you do have increased inflammation, so I think if you have a severe enough brain injury, this would be the point where you can give these treatments.
10:17 Torie Robinson
This is basic science though right? So, as in we don't want to get people too excited it's not something that's, you know, going to come on the shelf tomorrow.
10:26 Tobias Engel (10:08.749)
It is basic science and what we have seen now [is] that in our experimental models, in our animal models, it works really well. So then, I guess the good news here is that these antagonists (these drugs for this receptor); they have already been used in other brain diseases in humans. So, in clinical trials… this is in clinical trials for depression (as far as I know), and also, psychiatric diseases. But the bottom line is that these… so, what they have seen is that they are safe in humans.
10:55 Torie Robinson
Okay.
10:56 Tobias Engel
So, you can give these antagonists, there's no adverse effects (to date) what people have seen. So, this means that hopefully that the translation from animals to patients would be a little bit faster. About the timelines: I don't know. So, we are working closely with industry together. And these were also, in the paper what we just published here, they were involved in the paper, so they are developing these as clinical candidates (these drugs). So, the idea is hopefully that at some stage we can move forward towards clinical trials, but, this depends on, you know, we need of course input from industry and… but as I mentioned; as there are already clinical trials with this specific drug underway so, I would hope that it will happen at some stage, hopefully.
11:39 Torie Robinson
Mmmm.
11:40 Tobias Engel
The other part what we're doing now is to understand better how the receptor like, actually works in the brain. We know more or less what they do, but it's a, you know, each signalling system is quite complex. And to understand this: what we're trying to do now is really to know what this receptor does in each cell type. So, for example, we know it's important in microglia, it is highly expressed, we see it there, it induces inflammation, but these receptors are also, expressed on other cell types. So, we can find them on neurons, on astrocytes, and all kinds of oligodendrocytes on in the brain. And what we're trying to do here is to find out whether blocking this receptor on specific cell types, whether this is good or bad. Because, eventually, what we're aiming to do is really to target the receptor only where it's bad - so probably only at the source (microglia). This is one of the projects what we're doing at the moment, just to look at the specific cell types.
12:31 Torie Robinson
Ooh!
12:32 Tobias Engel
What we're trying to do is look at different cell types, you know, because, we know now that one thing is to give a drug, a generic drug, and it inhibits everything and sometimes it works or it doesn't. But sometimes you also, can have side effects and so on, and maybe this isone of the reasons maybe that in some cell types, these receptors are actually good, they're not bad. So, we have shown in different studies when you block it in a certain cell type, this was not really advantageous. So, I think going towards the source we know that inflammation here is the bad part, is trying to work this out, what exactly we have to block. So, this is one of the parts what we're doing in the lab as well, to just to, you know, make it later better, the kind of the delivery for our drugs.
The other part, what we're doing as well is (and this was part of the study), is what we want to do is we want to identify patients who would actually benefit from our treatment, right? So, one thing is developing the drug to see whether it has anti-seizure effects, but the other thing is also, what we want to see is: can we identify patients who are actually in need of this drug? Because, probably, it's not that every drug is good for every person, I would imagine.
13:42 Torie Robinson
Mm-hmm.
13:42 Tobias Engel
So, what we have done here is we have used PET imaging: PET imaging is you have a small molecule you can inject (this is also, used in humans, course, PET imaging for brain diseases, cancer and so, on). And what it does [and] what this molecule [does is it] binds to the specific proteins if you want to or you can [bind it to] whatever you want to bind it to. And then you have… you can do your imaging like an MRI and you can see where this accumulation of this protein is (of your molecule) and this will tell you what your protein is, for example.
So, what we have done in our study, what we've done here is we have induced TBI in our mice, right. Now animal models have induced TBI and then we have injected these molecules and performed PET imaging in these animals at different stages and these mice when you do your TBI these mice after a certain… after a couple of weeks/months, they will develop epilepsy. So, what we have seen is when PET imaging these molecules against the P2X7 receptor they were higher in these mice after the insert, these mice were more likely later to develop seizures.
14:46 Torie Robinson
Ahhh.
14:46 Tobias Engel
So, the idea here is that after a brain injury, you can maybe test for this P2X7 receptor PET imaging. You can test for this. Is it upregulated? And then you would know that this person may be more of risk of developing epilepsy, but also that they [would] benefit (hopefully) from the treatment against this receptor.
15:05 Torie Robinson
Thank you so much to Tobias - for sharing with us his exciting discoveries regarding the P2X7 receptor and how it could help prevent seizures, epilepsy onset, and more - amongst those who experience Traumatic Brain Injury in the future!
Check out more about Tobias and his work on the website t-or-i-e robinson.com (where you can also access the podcast, the video, and the transcription of t
his episode) all in one place, and…
If you haven’t already, don’t forget to like, comment, and subscribe to the channel, and share this episode with your friends/your colleagues/your family members/somebody down the pub/universities/anywhere - because this supports our mission to decrease the discrimination faced by and improve the quality of life of those affected by the epilepsies… aaaaand get everyone appreciating and encouraging funding for the incredibly cool epilepsy research out there!
See you next week!
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Tobias Engel is a Senior Lecturer at Royal College of Surgeons in Ireland, Dublin, where he has been working for the past 20 years.
He did my undergraduate studies in Biology in Germany and Spain and then his PhD on Alzheimer’s Disease in Madrid Spain (completed in 2005). Tobias then went to Dublin and did a postdoc with David Henshall at RCSI where he established his own lab about 10 years ago.
His main research focus is understanding the underlying pathological changes in the brain in epilepsy and whether targeting these provides disease-modification. A second focus of his is the identification of biomarkers to support the diagnosis of epilepsy and who may develop epilepsy.
They, as a lab,, are mainly interested in purinergic signalling via ATP and whether this signalling system can be used for the identification of new targets and diagnostic tools. Here, they have been working on the ATP-gated P2X7 receptor, ionotropic receptor expressed mainly in microglia where it contributes to inflammation. Over the past 10-15 years they have shown anticonvulsive and anti-epileptogenic effects targeting the P2X7 receptor in several preclinical models – this includes also studies suggesting disease modification.
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