Chemical Collective

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This is a Kun V studios original program.

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The content of this program does not reflect the views or opinions of 91.5 jazz and more the University of Nevada, Las Vegas, or the Board of Regents of the Nevada System of Higher Education. Box. Dogs.

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Welcome to chemical collective, where we explore the latest research and insights into the realms of neuroscience, mental health and the fascinating world of therapeutic chemical compounds. Our guest today is someone whose work is at the intersection of brain science and immune function and helping really reshape our understanding of neuroinflammation and its far reaching implications for mental health. We're thrilled to have Dr Kendra McLaughlin, an assistant professor in residence at the Department of Psychology University of Nevada, Las

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Vegas, holding both a PhD in neuroscience and a Bachelor of Arts in Psychology from UNLV, her academic excellence and dedication to research earned her an outstanding GPA of 3.8 and numerous awards, including the prestigious rebel grad slam scholarship and several research travel grants. These achievements reflect her commitment to advancing both her field of study and her educational journey, equipping her to make significant contributions to neuroscience and beyond.

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Dr McLaughlin's research is centered on understanding neuroinflammatory processes and the critical role of microglia, a specialized immune cell in the brain in various neurological and mental health disorders. Her work delves into the intricate balance these cells maintain, defending neural tissue in some cases, while contributing to brain dysfunction when over activated. Her studies are paving the way toward identifying biomarkers that could allow for early detection of neuroinflammation related diseases, and through innovative models, she explores how cycles of microglial stress and inflammation might predict disease progression and response to treatment, offering potential pathways for targeted therapeutic interventions.

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Moreover, Dr McLaughlin's dedication extends beyond the lab. She's passionate teacher and mentor, inspiring her students through hands on learning experiences and fosters inclusive educational environments in her classroom. Her commitment to diversity and representation in the STEM fields underscores her broader vision for collaborative, equitable future in science research.

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Today we'll be discussing her groundbreaking research, her insights into the role of microglia in neuroinflammation, and her hopes for the future of drug therapies and personalized medicine targeting these areas. Dr McLaughlin, welcome to the chemical collective. We're so delighted to have you with us.

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Thank you so much for having me. I'm delighted to be here

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to start. Could you share what initially led you to pursue neuroscience, especially your focus on your inflammation and microglia? Yeah,

Unknown Speaker 2:48
no, I love that question. Initially, my fascination for you know, the brain and how we think and feel things started a really young age, which naturally led me to study psychology in my undergrad. However, as I delve deeper into psychology, I came across one of my favorite courses where it was kind of the foundation of neuroscience, and that connection that we have from our brain and how we are able to move, and sometimes how that breaks down over time. And that was it. For me, I was hooked. So this idea of the brain as an organ and its relationship with our bodily senses, especially the immune system, was equally intriguing to me. So one of the things that truly captivated me was learning about microglia. So these are those immune cells in the brain that have an incredible kind of duality to them. They're able to protect neural tissue under normal conditions, but under more chronic stress or disease states, they can actually become harmful. So this more so duality in their function was fascinating to me because it meant that they could be both kind of like a hero and unintentionally a villain as a movie buff myself who doesn't like an unsung hero and you're, I guess, a villain in someone's story. But it prompted me to wonder, like if we could harness that protective quality of microglia while preventing their harmful actions and conditions of chronic activation. So this question has ultimately formed the foundation for my doctoral research that I went on to research

Unknown Speaker 4:28
that's super interesting, as you're saying, how something inherently protective, like an immune cell, can then contribute to harm? Can you talk a little bit more about some of the early experiences or insights that helped guide your work to where it is today.

Unknown Speaker 4:43
Absolutely So during my graduate studies, I was exposed to a wealth of kind of research that highlighted this role of inflammation in chronic diseases, so not only in the brain, but throughout the whole body. So it became clear to me that inflammation. Is not just this byproduct of disease. In many cases, it's kind of the driving force behind the progression of disease. This ultimately led me to focus on microglia and their role in inflammation, specifically as they are the primary immune cells of the brain, like you were saying, in the central nervous system and in the inflammatory responses, I instantly became more interested in how external factors like environmental toxins or chronic psychological stress could lead these cells to become overactive. So overactive microglia can create that state of chronic inflammation that has the potential to damage healthy neurons or other brain cells. This perspective is what helped me see that neuroinflammation not merely as that symptom of brain disease, but as a potential target for therapeutic interventions. And this realization opened up a new path for my research, pretty much focusing on ways to modulate or dial down microglia activity to protect the brain from the negative effects of chronic inflammation.

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For our listeners who may not be familiar, could you explain what microglia are and what role they play in the brain?

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Yeah, yeah, of course. So microglia are a unique type of immune cell that reside within the central nervous system, which includes the brain and spinal cord. So unlike other immune cells in the body that circulate through the blood, microglia are permanently stationed within the brain, or something called the brain's resident immune cells, or those first responders, because they're always on alert for signs of infection or injury or cellular debris. So under normal conditions, microglia play a crucial role in maintaining brain health. They constantly survey their micro environments, checking for signs of trouble, and are involved in clearing out dead cell cells and that synaptic debris. So when they detect a threat such as a pathogen or injury, microglia rapidly activate and release signaling molecules to either neutralize the threat or coordinate with other immune cells to respond effectively. So in situations of chronic stress or ongoing exposure to harmful stimuli, microglia can remain activated for prolonged periods, which can be detrimental. So prolonged activation leads to the release of excessive inflammatory molecules, which can start to damage that healthy neurons that we're so interested in so contributing to all of those neurodegenerative conditions that we know today. So

Unknown Speaker 7:40
that's fascinating. And again, I think one thing that's really important to think about is you're using two different words, neurons and glia, and these are really the two different cell types in the brain. But we're in such a neuron centric world right now, where people really only think about neurons. And when we talk about neurons, we talk about plasticity. So we're making new connections, new synapses. Sometimes we're ripping them apart. Sometimes we're leaving ones there that are bad. Sometimes we're leaving ones there that lead to learning and memory. So in glia cells, is there a similar adaptive role like plasticity?

Unknown Speaker 8:16
Well, they do have a large role in plasticity, in terms of being able to help prune and kind of see the way those connections that aren't as not relevant, I guess, in that way, they are super, super important when it comes to that, and kind of goes into, like their overall role of being able to either help or harm a system.

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So this is a form of adaptability, effectively, absolutely,

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the adaptability of microglia is beneficial for short term responses to injury or infections. So they can shift between different functional states, essentially, depending on what the brain needs, from surveillance to active defense or repair. So when the brain is exposed to those prolonged periods of stress we were talking about whether these injury or environmental factors, microglia can remain activated longer than necessary. This prolonged activation can turn them from protectors into potentially harmful agents within the brain. So chronic activation of microglia has been linked to a variety of neurodegenerative conditions. For instance, in diseases like Alzheimer's, microglia that initially act to kind of clear that amyloid plaques that we are known to see here can eventually become overactive, producing inflammatory cytokines that damage neurons in other cells. Other goals and research is to understand the molecular pathways that control this sort of shift in microglial function and find ways to modulate their activity in a way that promotes healing while reducing harm. It's a delicate balance, but it's essential for managing neuroinflammatory disorders,

Unknown Speaker 9:51
and I know you just mentioned how microglia can be involved in Alzheimer's. Can you give us some other examples of neurological disorders where microglia. Might be involved and discuss the implications of this for potential therapies, or even

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just start with the scaffolding of Alzheimer's disease and how that works.

Unknown Speaker 10:09
Yeah, so essentially, for Alzheimer's disease, initially, these cells, they attempt to protect the brain by clearing those amyloid plaques that we're just talking about, which are essentially toxic proteins that are clumped and kind of associated with this disease at its core. So the progression that we see in this disease, microglia can become chronically activated, shifting from a protective to function more so, exacerbating brain damage by releasing harmful cytokines and reactive oxygen species. So this inflammatory environment contributes to further neuronal damage, accelerating things like memory loss or cognitive design. We also see indications things like Parkinson's disease as well as MS or multiple sclerosis. Like in MS, for instance, microglia play a role in that immune response, by microglia activation essentially contributing to the degradation of myelin, which are the things that are achieving those neurons, leading to things like severe motor cognitive impairments.

Unknown Speaker 11:14
So it seems complicated, is what I'm hearing, because you don't want the microglia to become activated or aware too early, and if we get there too late, then the symptoms have already kind of happened. So, you know, it seems tricky. Yeah,

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absolutely,

Unknown Speaker 11:32
yeah. And so it seems like these disorders are really protracted over long periods of time, and by the time that symptoms are actually apparent and a person's in the clinic, I'm getting the sense that these cells have already been activated for quite a while. Is that why early detection is so important in these conditions?

Unknown Speaker 11:52
Absolutely, by the time we observe symptoms like memory loss or motor impairments, neuroinflammation and microglue, activation may have already been ongoing for years or even decades. Yikes, now a significant amount of neuronal damage may have already occurred at this point. So this is why earlier biomarkers of neuroinflammation are so critical to find. If we can detect neuroinflammation before extensive damage is done, we can intervene much earlier in this disease progression?

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Yeah, I know what diseases too, like Parkinson's, by the time they become symptomatic, over 75% of the dopaminergic cells are lost, right? Yeah. So, you know, I think the problem is the microglia cells at some level. But I think what you're headed towards right in your research is understanding the earlier markers before we lose all those cells.

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And I wanted to talk a little bit more about neuro inflammation, if that's all right, I'm wondering how it connects to mental health conditions like depression or anxiety. That's a great

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question. Oh, yeah. So this is an area of neuroscience that is generating a lot of interest, especially as we learn more about the connections between chronic inflammation and mental health. So studies have shown that chronic stress can lead to prolonged activation of microglia, which release neuroinflammatory kind of molecules that can affect brain regions involved in mood regulations, including the prefrontal cortex and the hippocampus, so these inflammatory signals can disrupt that balance of neurotransmitters, potentially contributing to those mood disorders like depression and anxiety. So in cases where there's treatment resistant depression, we often see elevated levels of pro inflammatory cytokines, which suggest that neuroinflammation might be a contributing factor. This could help explain why some patients don't respond to traditional treatments, which primarily target neurotransmitter systems like serotonin. If neuroinflammation is a factor in these cases, targeting it directly, could offer a new treatment Avenue, particularly for individuals who haven't found relief with conventional therapies. We touched on it a little bit earlier, that neuroscience is very neuron centric and kind of finding treatments for various disorders, and that we should pay attention to glia and maybe now inflammation. So it sounds like we should really shift the way we think about treating mental health conditions. Could targeting inflammation change the traditional approaches we currently rely on absolutely so. Traditional treatments for mental health disorders have primarily focused on regulating neurotransmitter levels like serotonin or dopamine, like Dr Hines was saying, however, if we consider the neuroinflammation might be an underlying cause of contributing factor, if you will, for some patients, then addressing both inflammation and neurotransmitter kind of imbalances can offer a more comprehensive treatment approach. So for individuals with treatment resistant depression, incorporating anti inflammatory agents into their treatment plan could address the underlying neuroinflammatory component of their symptoms. This approach may open up new treatment possibilities. And provide relief to individuals who haven't responded to those existing medications. And, you know,

Unknown Speaker 15:05
that's kind of fascinating, changing the stigma, where, you know, we've taken people with major depressive disorder and said, Well, it's just a lack of will and morality, you know, serotonin, but now clearly cytokines and inflammation are involved, so this is truly a sickness, right? So I think even that perspective alone is super helpful. So Kendra, the name of the show, is the chemical collective. So we like drugs. We talk about drugs. We think about drugs. Could you maybe talk about some of the promising drug therapies around neuroinflammation that are currently being developed?

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Yeah. So there has been tremendous progress in developing therapies specifically targeting neuroinflammation, and it's a very promising time for research in this field. What we see is one approach that has shown potential, and it involves the use of tsbo modulators. So tsbo, or translocator protein is located on the outer mitochondrial membrane, so that powerhouse of the cell like that, and it's primarily in immune cells like microglia that we've been talking about. So when microglia become activated in response to brain injury or disease, TSB expression increases, making it an ideal target for modulating immune responses in the brain.

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I know you said about say it again. What is this? Tspo? Can you tell us a little bit? Yeah,

Unknown Speaker 16:28
yeah. So tspo is translocator protein, and it's essentially very, very prominent on this immune cell that we've been talking about. And what we know is that it's had a long history going from being peripheral benzodiazepine, all of those things, but a lot of research has gone behind it to more so focus on what its role might be in inflation specifically. And

Unknown Speaker 16:51
it's kind of sort of like a bicep at some level, right? So if the mitochondria is working harder, it gets a bigger bicep, right? And if it's not exactly,

Unknown Speaker 16:58
exactly that. And so the idea is that by targeting tspo, we can selectively reduce the activation of microglia. So that means that we can be able to modulate it, essentially.

Unknown Speaker 17:11
So how did research initially identify tspo as a therapeutic target? Yeah.

Unknown Speaker 17:16
So essentially, we were able to find this correlation between it and we've been able to see different types of ligands that directly impact this, such as tsbo, ligands like map mill or xbd 173 they've been able to show promising results in pre clinical trials, Reducing the release of inflammatory cytokines and limiting neuronal damage, of models of different types of neurodegenerative diseases. And a lot of research has been able to try to be aimed here, to characterize what tsbo does.

Unknown Speaker 17:52
And some of your research is around some of those molecules. Those are a mouthful. Can you say them again? Sorry.

Unknown Speaker 17:58
One that I mentioned was, are you talking about a mapanil? Yeah, so a mapanil is considered to be a really fascinating development, and essentially it was working primarily on as a compound that affects microgliactivity In models of neuroinflammatory diseases. So for example, in animal models of Alzheimer's disease, we have observed that tsbo ligands can effectively reduce the release of pro inflammatory cytokines from microglia. So cytokines are signaling molecules that, in large amounts, can exacerbate inflammation and damage neurons by decreasing these cytokines, tsp ligands like a mapping can create more protective environment for neurons slowly the neurodegenerative process. So

Unknown Speaker 18:51
I know we were talking about mitochondria and amapimil and tsp and all these things, but another super exciting area that people are talking about right now are the cannabinoid based treatments, especially around the CB the cannabinoid two receptors. Can you tell us about some of these cannabinoid based treatments and how they fit into potential neuroinflammatory therapies?

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So cannabinoid based treatments are rapidly growing area in neural inflammation, as you mentioned. So this endocannabinoid system is involved in many physiological processes, including inflammation, pain and mood regulation. So cannabinoids that specifically target CB, two receptors that you mentioned, which are located primarily on immune cells like microglia, offer a unique way to manage neuroinflammation without the psychoactive effect associated with CB one receptor activation, which is typically caused by things like high associated or high associated with cannabis, excuse me. So these CB two targeted therapies are showing promise and reducing. Neuroinflammation by modulating immune cell responses. So when we activate these CB two receptors on microglia, these cells reduce their production of pro inflammatory cytokines, leading to less damaging immune responses. The specificity for immune cells in brain kind of allows us to address our inflammation without affecting our cognitive or behavioral functions.

Unknown Speaker 20:26
So we've been talking a lot of like about pre clinical research. So can you tell me about what this would look like in the clinic, and, you know, identifying people at early stages? So could you tell us more about the role of biomarkers in tracking neuro inflammation and how they might improve early detection.

Unknown Speaker 20:44
So biomarkers are essential tools in modern medicine because they provide measurable indicators of disease progression or therapeutic efficacy in neuroinflammation. Potential. Biomarkers include pro inflammatory cytokines, which can be detected in body fluids like blood or cerebral spinal fluid. When we see elevated levels of cytokines such as like a il one beta or il six or TNF alpha, they can signal an inflammatory response in the brain, offering that window into state of that inflammation, imaging techniques like PET scanning, using tsbo tracers allow us to visualize microglial activity in real time. Tsbo tracers are designed to bind specifically to activated microglia, enabling us to sort of detect areas of inflammation within the brain. This imaging is particularly valuable, I'd say, for understanding the extent and location of neuroinflammation, which can inform treatment decisions. Biomarkers could eventually be used to not only diagnose neuroinflammatory conditions early, but also for monitoring how well a treatment is working, allowing us to tailor therapies to each patient's need. So

Unknown Speaker 22:00
I want to go and talk a little bit more about the treatments we are discussing, like tspo ligands or cannabinoid trace based treatments. What challenges exist in bringing these therapies from the lab in, from research to then clinical practice? I

Unknown Speaker 22:16
see okay. So one of the biggest challenges we face in right now is probably the blood brain barrier, or the BBB. It's a protective shield that restricts many substances from entering the brain. While the BBB is essential for protecting the brain from pathogens and toxins, it also limits the effectiveness of many drugs as they can't easily cross this barrier. So Researchers are currently exploring various delivery systems such as nanoparticles or liposomes to be able to help with this and tsbo ligands and cannabinoids bypass this DVD and reach the brain more effectively.

Unknown Speaker 23:00
So another cool thing that I'm really aware about you is that you're very interdisciplinary, so that you're able to kind of go from not just neuroscience, which, by the way, is a huge, you know, interdisciplinary field, everything from anthropology to physicists. So you were able to kind of get into various engineering models and employ them to understand these things that you know me and April talking about with you earlier that it's really complicated to understand acute, chronic stages. Could you just tell us a little bit more about that and how you used engineering to understand really microglia stress?

Unknown Speaker 23:32
Yeah, and that's honestly one of my favorite things about neuroscience is how interdisciplinary it is. Our team was able to use engineering based models, particularly from material fatigue studies, so we wanted to use this to better understand how chronic stress may impact microglial function, just as kind of materials can weaken over time. Under repeated stress, we hypothesize that microglia experience fatigue when they are chronically activated, and this prolonged activation can shift from a protective to harmful role, which like how all material might begin to fail or after that repeated use. So essentially, by applying engineering models, we aim to map out how microglia transition from beneficial protective states to ones that contribute to inflammation and neuronal damage. This approach allows us to pretty much predict critical points at which microglia might become detrimental.

Unknown Speaker 24:32
And speaking of these critical points, so in terms of early intervention, what are the potential benefits for patients if we can detect neuroinflammation earlier using models or something else.

Unknown Speaker 24:41
Yeah, earlier intervention is potentially transformative for patients dealing with neuroinflammatory diseases. So neuroinflammation can lead to significant neural damage, like we've said, but if we catch it earlier, we could have a much better chance at preserving brain health from progressive diseases. Like Alzheimer's and all the things that we've talked about along the way,

Unknown Speaker 25:04
super cool. So I think we would be bereft if we didn't talk about the major class of inflammatory molecules. NAS adds, can you talk a little about NAS, what they are traditionally, and some of the things that they use,

Unknown Speaker 25:17
absolutely so traditional naysayers like ibuprofen or naproxen or aspirin are effective at reducing pain and inflammation because they inhibit enzymes that are more so the COX enzymes, specifically one and two these enzymes play critical roles in producing prostaglandins, which are lipid compounds that contribute to inflammation, pain and fever, but exhibiting pretty much inhibiting those COX enzymes these ads lower the production of prostaglandin and reduce inflammation. However, this inhibition does come at a cost sometimes, yeah, prostaglandins

Unknown Speaker 25:56
and COX inhibitors, and I know all these ace things, this is the biggest movement in Alzheimer's disease right now. So huge field. Yeah,

Unknown Speaker 26:03
and as we've been discussing, it sounds like there's a real need for innovative therapy. So what are some of the novel NSAID therapies being developed to address these issues? Yeah,

Unknown Speaker 26:13
there's a lot of exciting work being done in this area. One of the key developments has been the creation of Cox, two selective inhibitors which pretty much improve safety profile. So traditional, nay said, inhibits both those Cox one and two, like I mentioned, those enzymes, but Cox two is the enzyme mostly involved in inflammation by selectively targeting this one. These newer drugs reduce inflammation without impacting Cox, one, which is crucial for things like stomach protection and kind of that stomach lining is very involved with that. So drugs like Salo Cox, which were known to be the most or the first Cox two inhibitors, and while they're pretty effective. They have been linked to things like cardiovascular risks. That's fascinating. So

Unknown Speaker 27:05
what about these, nay said, targeting specific pain pathways or delivery systems to reduce side effects?

Unknown Speaker 27:13
Yeah. So target delivery systems are another promising area. One approach involves using nanoparticles, like I mentioned earlier, liposomal delivery systems to transport these naysayers directly to the inflamed, inflamed tissue. So this being encapsulated by these naysays in the neural particles, or the liposomes, the drugs can be directed more precisely, to areas of inflammation which reduce the amount of medication needed and consequently lower the risk of systematic side effects. And

Unknown Speaker 27:45
Dr McLaughlin, we're always terrible on the show. We always bring everything back to five HG, two, A, it looks like Cox two, and the liposomes are highly regulated by Sir One, 5h, two, a receptors. So some of the most novel compounds right now for Alzheimer's disease, relate to five, HT, two, a this has been fascinating. Thank you so much. This has been another amazing episode of the chemical collective. Hope you enjoyed it. Take care.

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