Doctor at LSU Health Neuroscience Center, Nicolas Bazan, MD, PhD talks about ischemic strokes.
Interview conducted by Ivanhoe Broadcast News in 2023.
Tell me what is it that ischemic stroke does to the brain?
Bazan: The ischemic stroke is very common; we have about 100,000 cases per year in the United States. What they will do is cause the blood flow to a specific area of the brain to diminish all of a sudden. Due to a blockade of a key artery and the supply of oxygen to that area of the brain produces transient damage. Some areas of the brain that we call penumbra are partially damaged. Other inside the brain, the core is more damaged. The penumbra is transiently damaged because the low blood flow produces the onset of damage. It’s an area that we call that could be potentially rescuable, that perhaps there are experimental treatments that we can try to protect that area and then be able to restore function of that area. So obviously, the area of the brain affected by ischemic stroke is very important in motor function. Those are some of the consequences of stroke. Also, longer-term consequences that we are very much interested in would be cognition changes happening in the brain as time goes on. Particularly in older individuals, the cognition changes are very worrisome, because some of them could lead to dementia-like states. Yes.
That’s something that I haven’t heard of before you hear about not being able to one side your speech is affected. But I haven’t heard about the long-term effects on your brain.
Bazan: On cognition specifically. Yes, absolutely. That’s very worrisome. Out of those 800,000 patients, about one-third of those, unfortunately, do not survive after an ischemic stroke. One-third of them, remarkably with physical therapy and so on, will slowly recover. hat what told us a few years ago. Well, perhaps that group of patients is giving us a message that the brain may set in motion internal mechanisms that will turn on the protection mechanism, we call it neuroprotection. That’s how we began the search for new molecules that the brain could produce to protect itself. Yes.
How does that differ, I hate to even date me like this, but two decades ago the drug came where you’re having a stroke and you get it within a certain amount of time that it could reverse the effects of the stroke.
Bazan: We are still using that medication and what that will do is restore blood flow to that area of the brain. Unfortunately, only five percent or a small percentage of the patients with an ischemic stroke are eligible for this therapy. Most of them are not eligible. We are still using that. Also, a new way that surgeons, actually vascular surgeons and cardiovascular surgeons have developed is to introduce a catheter. Try to go to that artery of the brain and tear down the catheter to restore the flow. We call it the thrombi that is blocking the artery. This is a new experimental approach that is very much being studied nowadays because it brings us a therapeutic opportunity. However, restoring the blood flow suddenly to that area of the brain is good and bad. Having a lot of oxygen flowing again through that area of the brain generates brain molecules that could be damaging. We call them free radicals. It’s a double-edged sword that thrombolytic therapeutics, although there are opportunities. We have developed a concept and we have developed several intellectual properties, and several patents, by which in the thrombolytic approach, we can inject into the brain neuroprotective molecules that we have discovered, and we are studying nowadays. This is an area that opens a lot of avenues, potentially useful for the near future, from a therapeutic point of view.
Bazan: The extended trial is very important, we just submitted, actually ran to NIH on the extended trial, because what this does is the therapeutic that only affects about five percent of the patients can actually, which we used to think is a few hours will go to 10, 15 hours. It extends the therapeutic window, and during that extended therapeutic window will allow us to use other neuroprotective compounds that we can use directly to the brain or systemically or internationally. We are also using the international approach to reach the brain faster. In experimental models of the ischemic stroke.
Now I’m reading, which seems amazing, that you’re hoping that this could even extend out to like seven to eight days.
Changes the game forever.
Bazan: Totally, and that is what is under investigation at present because some of the compounds that we discovered that the brain makes is a new family of molecules that we call elovanoids. These are derived from omega-3 fatty acids. Instead of being shorter chains, these are very long chains, 32, and 34 carbons. What we have done chemically, instead of double bonds, we made triple bonded molecules. Trying to have bioactivity, and neuroprotective bioactivity for an extended period. It is too early to say, but experimentally we can expand the window of neuroprotection. And we are currently intensively studying these molecules and related molecules. Because we have tools in the laboratory, very new tools. We just reviewed data yesterday on tandem mass spectrometry. We have as many 200 new molecules, that are being generated under these conditions.
Bazan: Essentially, I’m telling you that in that extended time, the brain is making molecules that we didn’t know it was making. We’re trying to single them out and see the potential complementary neuroprotection to give us an extended window of protection against ischemic stroke.
Will that be able to, and you’ll have to let me know how ischemic stroke works? Does it go in and immediately that part of your brain dies? Or do you have time? Or would you have to bring that part of your brain back to life? What would they be able to get back in your hopes?
Bazan: A part of the complexity of our brain response is due to how our brain functions. The key element in the area that stroke targets is a connection between neurons that is called the sinus. The sinuses we have many in our brain are neurons interconnected that send information from one to the other. Around them, there are a multitude of other cells, astrocytes, microglial cells, and oligodendroglial cells. We have cells of the vasculature. The response of the brain to damage is not only one element, but also a multitude of cells that are responding. Truly, we don’t understand where the initiation of the damage happens. However, we suspect that the drivers are microglia, damaging microglial cells, and perhaps astrocytes that are not performing well. As a result, the sinuses, the connection between the neurons, and the communication between them is impaired in circuits in the brain. We are using an Ischemic stroke now, a new approach which is called single-cell genomics. We are trying to separate the brain’s 10, 20, 30, 40 cells and different cells, and trying to see the phenotype of each cell, which is protected, and which are damaging. Not only microglia but astrocytes as well. Our concept is that this constellation of cells around the sinus, when they are behaving in a protective mode, will be forming mediator signals that will protect the circuits of the brain. Single-cell genomics is a very important approach that we develop in the laboratory, and we are going to be communicating some of these results very soon. The second aspect is that we can also look at genes that respond because of other factors because stroke is a very important comorbidity. For example, somebody that has diabetes or somebody that has hypertension. We call these other responses epigenomics because they are not just the genes, but other mechanisms that happen in the brain. I believe that approach will teach us many unknown responses of the brain from the point of view of these signals that allow the integrity of the function of the brain to be sustained after an ischemic stroke. Of course, we also have other models in the laboratory like traumatic brain injury, we have models of Alzheimer’s disease and of other diseases where we are trying to learn by using these various multidisciplinary approaches. As you might imagine, we must use extensive machine learning and many algorithms to be able to deconvolute the complexity of these literally thousands of cells that we are getting through these single-cell genomics and epigenomics.
Before I think about everybody, one of the scariest things that you can think about happening to you because you know that the damage is so bad but you’re still living, right?
Bazan: Yes.
You have to live with the damage and what you’re doing is trying to help people live up lifestyle but so much better?
Bazan: Yes, and one issue from a clinical point of view is that as we age, often mainly due to comorbidities, there are mini strokes that people could have. Those mini strokes are associated with cognition changes. At age 65, one age is beginning to have mild cognitive impairment, and often many of those clinically have been demonstrated that are linked to having already mini strokes in different areas of the brain that will not produce the same magnitude of symptoms as a major ischemic stroke in the area that I described at the beginning. Yes, this is a very important problem that we have in medical sciences now. Fortunately, we have tools and in our laboratory, we have discovered these new neuroprotective molecules that I believe open avenues that have a therapeutic potential.
Perfect. Leslie, anything you can think of?
Leslie: I was talking about the silver bullet.
Bazan: Is very quickly, because the idea is that you can study mechanisms in stroke and try to clarify this immense complexity of how the brain responds. What we stumble is a new molecule that is neuroprotective. In the lab, we call them silver bullets because we actually have the chemicals in our hands that we can inject into an experimental model of stroke or we can administer them internationally. I set up for you a cartoon that Leslie can send to you where the different cells and genes that are potentially involved in the publication. Perhaps Leslie, you can send that?
Interviewer: Perfect. Thank you.
Bazan: I’m lucky to be surrounded by all of these people that you will see in the lab. I’m surrounded by a lot of talented young people who are very dedicated and have a clear purpose in medical science. So, thank you so much.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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Leslie Capo
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