Good afternoon. My name's Dr. Cameron Jones and I'm an environmental microbiologist. And this week on the live stream, I had some really fascinating research that I want to bring to your attention. And it is focusing on another type of problem that has a strong microbiological underpinning. And it is particularly important because we're going to be focusing on not just infections and asthma-related respiratory problems caused by fungi, but we're going to take a look at how these are possibly linked to a range of different brain diseases or brain disorders. And so the topic of today's live stream is how a common anti-fungal drug could help stop brain diseases.
To put this in context, I want to share a bit of a personal story with you because many years ago, when I was doing some postgraduate training in industrial microbiology, one of my lecturers was Warren Baker. And I want to tell you this personal story because it sets in context why I'm bringing you this live stream and why this has always been a topic that I have been very interested in. Warren Baker was one of these classic academics. He was a chemist by profession and he had very dense lectures that he used to bring to us. He had an encyclopedic knowledge of chemistry. When he retired, I heard soon thereafter that what caused him to retire was because he had early-onset dementia. Obviously this impacted severely on his ability to enjoy his retirement, and it ultimately was the reason that he eventually passed away.
And if we look at the experience of brain disorders here in Australia, over the next 40 years, they are going to cost us approximately $1 trillion. And get this, 16.4 million Australians are going to end up being impacted by various different brain disorders. And so the live stream today, I want to focus on some breaking research and this really is fundamentally important research because it is something which many of you want answers. And without medical intervention, there isn't going be any way of reducing the severity or the impact of these various different brain diseases. Because a lot of the treatments that medicals can give you really just slow the progression, but they don't stop it. So scientists need to come up with answers to this. And so that is the topic of today's live stream.
Okay. What are we focusing on?
I need to give you a bit of first principles about brain biology. Well, the brain consumes approximately 20% of the body's energy. Now, put another way, this means that your brain uses approximately 20% of the oxygen and blood to sustain it. 25% of that energy goes to help maintain the cellular processes going on inside your brain, and the other 75% goes to the signaling. And that is how we actually learn, retrieve memories, and actually the whole process of cognition. So think of that. 75% goes for the signal transmission and 25% goes to supporting the cells. So when we're looking at what could go wrong, really it's one of those two outcomes: signal transduction or maintenance of cellular control.
Now neurological disorders are increasingly recognized as a major cause of death and disability worldwide. And to put this in context, an outstanding publication came out in May 2019, which essentially reviews the impact of neurological and neurodegenerative disease on a worldwide basis. Now, a lot of the links to these papers are going to be in the show notes at the bottom of the live stream. And certainly, if you are listening to the podcast, they'll be in the show notes there. But for those of you who are tuning into the live stream now, I'm going to make sure that the references are all put up after the live stream. And so you can retrieve these papers yourselves, and you can validate that what I'm saying to you is in fact relevant and potentially relevant to you or a loved one, because you might want to bring this to their attention.
And so this particular publication is looking at the global burden of these diseases on humanity. And they're talking about the fact that as of 2016, the range of neurological disorders are the leading cause of DALYs. And this is disability-adjusted life years. And essentially, think of this as the years lost when you could have been having good health. And so there are 276 million years lost. Think of that. And then it causes 9 million deaths. This is just a horrendous number and is really underappreciated. And that's why I wanted to focus this week's live stream on this range of neurological diseases because they are not well discussed. And certainly, we're putting so much attention now focusing on SARS-CoV-2, another type of pathogen.
In a sense, the cutting-edge research, which is coming through now is suggesting that a lot of these neurodegenerative illnesses and diseases may in fact have a strong microbiological component. And I think my old Professor Warren Baker would be very pleased to read about this in the literature because the paper that I'm focusing a lot of attention on is focusing on a chemical and its mode of operation is antifungal. I think he would have liked that, but for all of you who potentially have loved ones who are currently or potentially suffering from dementia, or Alzheimer's, or a range of different adverse brain issues, this research is something that you should be aware of and certainly, you should discuss this with your healthcare provider and medical doctor.
Now, what are some of the solutions that are hiding in the research literature?
Well, one of the papers came out in 2020, and this is looking at one of the components that I mentioned before. As I said, there's signal transduction, and then there is the maintenance of the cells themselves. And so this publication is providing two opportunities to modify the way these cells behave within the brain. And that can only be a good thing. And again, as I mentioned, for those just starting to tune in, the literature references to this will be in the show notes to this live stream and in the podcast. But this publication just came out a couple of months ago. And what it is stating is that there are two treatments for changing the mitochondria. Again, I've done whole live streams on mitochondria, but mitochondria allow the cells in your body and your brain to utilize oxygen and convert this into energy. And there is a whole range of disorders, including some induced by environmental fungi that are considered mitochondrial illnesses in that they disrupt the normal behavior of the mitochondria at the cell level. And this publication is suggesting that Alzheimer's disease, traumatic brain injury, depression, and Parkinson's disease all fall under those illnesses that have a very strong mitochondrial dysregulation.
Now let's go back to Biology 101. In all of our cells, we've got a range of objects called organelles. These organelles allow the cell to carry out its activities. And one of the types of organelles in all of our cells, including our brains, is something called the mitochondria. And this strange word allows this organelle to do something very important and powerful in our bodies. And it takes in glucose or sugars and oxygen and converts it to carbon dioxide, water, and energy. And this then allows the cell or the brain cell to carry out those functions like signal transduction. And so the point of these papers is that they are trying to positively interfere with the mitochondria to get them to behave properly or to behave more in a normal manner. And if they do this, the aim here is to improve these negative neurodegenerative outcomes.
And so the point of this publication in June 2020 is to use a dye called methylene blue, and then something called photobiomodulation, which is a variant on something called photodynamic therapy. And for any of you who don't know about photobiomodulation or photodynamic therapy, I urge you to key in these words into PubMed and retrieve some fascinating research on the impact of photobiomodulation. But in a nutshell, it is using light to positively interfere with brain activity. And when I say interfere, it is to reset the mitochondria in a sense. And things like methylene blue, which themselves are well-known antifungal, have well-known antifungal properties, show good potential of being able to change the mitochondria from a dysfunctional state to a more normal functional state. And there's some excellent fundamental research appearing in the research literature. I urge you to look into this.
Now, I want to take you onto another story in the journey of the relationship of pathogens to adverse brain behaviors. And one of the papers is on Parkinson's. This came out a couple of months ago and Parkinson's disease affects 6 million people worldwide. And the adverse symptoms really are movement disorders. But what this research is showing is that in the brains of people with Parkinson's, they have been able to determine that they are innocents invaded with fungal pathogens. And if we look at some of the tables extracted from the publication, it is a lot of the common fungi that we see in water-damaged buildings.
Now, I'm not stating that definite exposure to humans to water-damaged buildings is going to cause Parkinson's disease, but there definitely is a connection with a lot of the common fungi found in these known habitats that have adverse health impacts, especially on the respiratory symptoms of people. And those with Parkinson's disease are showing a lot of this same dominance of microbial invasion. And you can see Alternaria, Cladosporium, Penicillium, Aspergillus, various different candida microorganisms. Why are these microorganisms overrepresented in what is considered essentially a sterile area inside the brain? This is very, very important research because it is suggesting that there is something called polymicrobial invasion, which may predispose individuals to develop these adverse brain dysfunctional symptoms. And polymicrobial invasion may come down to the fact that an individual had a long history of being subjected to conditions that were micro-biologically unfavorable, meaning that they had illnesses caused by various different microbes.
There's another school of thought that the number of illnesses throughout one's life that are caused by bacteria, yeast, and fungi could conceivably predispose this cohort to develop abnormal brain problems. But I want to put this in context because as you know, each week, I talk about water-damaged buildings usually, and we can just pick one of the excellent papers from 2007. And this is talking about research from 2004, essentially 16 years ago. And in the United States, the economic impact of water-damaged buildings and the adverse impact of mould exposure on people costs approximately $3.5 billion annually. And the key modifier here is to maintain water-damaged buildings and dilapidated and put them into a fit and proper state.
So there is a general consensus in the academic and medical research community that exposure to dampness and mould substantially increases the risk and predisposes people to suffer a range of adverse health symptoms. But what if the impact of these bacteria, yeast, and fungi, goes beyond allergy, goes beyond sinus infections and impacts potentially on the brain? And we just have to look at one of the major think tanks around fungal pathogens.
GAFFI in the United Kingdom, they are champions of making a connection between exposure to fungi and the adverse impacts on human health. And they state clear research that fungal pathogens cause 1.5 million people to die annually. Fungal diseases were relatively rare until the 1950s with the introduction and widespread use of antibiotics. Which as we all know, leads to antibiotic resistance, meaning that these microorganisms, that the antibiotics were meant to kill and control, they've adapted to those chemicals and now they're even more virulent. As well in the '50s, advances in intensive care, advances in cancer therapy, the use of corticosteroids, all create immunocompromise. Various different aggressive cancer therapies also use agents, which cause widespread immunocompromise. And this is leading to more fungal infections in immunocompromised individuals. So fungi do more than just causing fungal allergy. They also cause direct infections like sepsis. And to put this in context, 150 people die every hour from fungal infections.
But now we come up to the climax of today's live stream. This paper came out two days ago on the 14th of August, 2020. Again, you're going to want to retrieve this yourself, for anyone that you know who is suffering brain disorders, bring this to your medical practitioner, to the clinician, talk it over with them, find out how they can potentially incorporate this into treatment modalities. But as a microbiologist, I think that this is fundamental cutting-edge science. I think it's a wonderful, wonderful publication. Let me get right into what this publication says.
Put this in context, dementia is a bit of a catch-all term. It's considered to be an age-related disease and there are lots of different types. Most of the drugs and treatments only delay symptoms. And this concept of brain inflammation is certainly considered a new target location for drug development. This neuroinflammation is very similar to what we are seeing emerging in the fungal water-damaged building issue of neuroinflammation, biotoxins causing inflammation either in the respiratory tract or causing issues like chronic fatigue, which are considered to have a very strong inflammatory component. So you can see that there is a strong connection with these pathogens and other issues that are not even considered related to brain dysfunction. But in this publication, they're saying the scientists are providing very clear evidence of how they can modify the negative impacts of dementia by modifying neuroinflammation.
I'm going to just jump into some of the key research. And like a lot of medical and scientific research, they use a model which is mice, and we really have to thank the 40 mice that participated in this particular research. And I want to talk about the two experimental systems that the mice were put into so that the scientists could determine the impact of memory loss and the dementia-related Alzheimer's disease type symptoms that they needed to induce in these mice to work out whether a drug that they gave them could in many cases, reverse or counteract the Alzheimer's disease type symptoms.
So just think about this. There are 40 mice, they were placed in two different types of experimental chambers. One is called a Morris water maze. And just to describe what happens to work out the relationship with memory, is that the mouse is placed into the water maze. Obviously it doesn't want to swim in the water. There is a platform submerged at some location within the water maze. So once the mouse swims to the platform, it obviously no longer needs to swim. Now the scientists use a camera to film how long it takes and where the mouse actually swims to. Because over time they do this on different days and they can determine whether or not the mouse can remember where the platform is and how long it takes the mouse to get to the platform on different days.
The other type of experiment is by placing the mouse into essentially two rooms, one which is light and one which has dark. And one of the rooms has a negative experience. And so the aim here is to work out how long it takes the mouse to remember that when it goes into that room, in this case, the dark room without the light, it gets a shock. And so it obviously doesn't want to go there and get a shock. So again, the aim of these two experiments is to measure the ability of the mouse to remember the negative consequences of not being able to work out how to knock at the shock or continue to have to swim around until it finds the platform.
So what is this breakthrough drug?
Well, it's called miconazole. Now, you're probably thinking, "What on earth is miconazole?" Well, the chemical formula is on the right-hand side, but it is the active ingredient in Daktarin. It is the active ingredient in common pharmaceutical, pharmacy-based antifungal medications. It's commonly used to treat skin infections, yeast infections, and ringworm. All of us have probably used it at one time or another.
Now, I'm not suggesting that you go out and get some Daktarin and rub it on your head or eat it or inject it. You do want to take this publication though to your healthcare provider or your medical doctor and discuss it with them. Find out how, and where, and what the opportunities for this new drug are. As I said, the paper came out two days ago. I don't imagine that it is currently applicable for people quite yet, but it will be I'm sure. And this is really breakthrough research from a microbiological point of view and from the viewpoint of standard science, this is outstanding research. I'm going to explain to you why.
The key findings show that miconazole attenuates memory impairment in mice, where they induce Alzheimer's disease. And just think, as you're looking at these slides, I'm going to put up the next couple, LPS-treated mice, this is a way of chemically inducing Alzheimer's disease or dementia. And the legend is color-coded in the bar graphs that I'm putting up. Obviously the control mice, nothing happens to them. They're just left normal. The MCZ mice, they are injected with this miconazole. This is the experimental drug, the antifungal drug. The LPS mice, they're the ones who are induced to have dementia. And then we have importantly, the red-colored bar graph. These are those mice that have dementia. They have induced dementia symptoms in the mice, but they also give them the miconazole.
And look at the testing trial in the mice being able to remember that they don't like getting shocked when they go into the dark room. And you can look at the height of the bar graphs, which shows the step-through latency, how long it takes them to make a decision to stay on the light or go into the dark. And you can see that for the normal or the mice given the nothing or given miconazole, they show a fast response. The poor old mice that have induced Alzheimer's disease, it takes them a long while to make a decision on which room to go to. But those mice that are responding to the drug, even after a short period of time, adjust under the normal control group. And that is fascinating breakthrough research showing that this drug attenuates memory impairment.
Let's look at another key set of findings. Miconazole reduces neuroinflammation in the hippocampus of the mice. Now, what is the hippocampus? Well, this is the area of the brain that regulates motivation, emotion, learning, and memory - a really important region of the human brain and obviously in the mouse brains as well. And so again, looking at the color coding here, the LPS they are the poor old mice that are having an induced brain injury. And you can see that the amount of neuroinflammation in these...
Hello again, we had a slight power failure. So I guess this is COVID ISO lockdown problems. In any case, I'm going to continue on with the final few slides talking about the potential impact of miconazole and what happened to these mice. And so I was just getting around to talking to you about how in the mice which had been unfortunately induced to have a brain injury, they wanted to look at the neuroinflammatory response in these mice. And so they looked at something called protein expression. And on the right-hand, bottom part of this slide, this is a gel electrophoresis, and the density of the colors or the bands shows you how much protein expression occurs. And you can see that in those mice which have dementia problems, you have a huge amount of protein expression. This is shown in the blue graphs. But in those mice which are given miconazole, that is the red graphs, the amount of protein expression reduces. And this is really, really, really fundamental important information.
Now, I just want to check before we interrupted about the previous graph. We were talking about the hippocampus, about motivation, emotional learning, and memory. And in these sections, when they actually stained the sections of the brain, they were able to determine that there was far less neuroinflammation in those mice that were treated with the miconazole.
And so the final graph, as I said, is talking about something called cytokine response. And any of you who have been following the SARS-CoV-2 virus impact has probably heard about cytokine storm. We know that cytokine storms occur when the body is under attack in a sense or it's mounting an immune challenge. And so they're able to determine that increasing the concentration of miconazole reduces the cytokine production. And by reducing cytokine production, you are reducing the inflammatory impact on the brain.
So what did the scientists conclude in this landmark study?
It states that MCZ or miconazole could inhibit this iNOS expression. Remember this iNOS expression leads to the inflammatory neurodegenerative condition in the mice brains. And so they're suggesting that of course, more research needs to be done, but they are suggesting that treating the mice with miconazole demonstrates a strong anti-inflammatory response and leads to memory improving affects. And overall, it is an appropriate and effective way to control neuroinflammation and hence prevent the progression of Alzheimer's disease. And the key take-home here is that miconazole because it is a readily viable drug that has already shown safety for topical use, may easily be repositioned as a drug to be used for the treatment of Alzheimer's disease.
I think that this is one of the most interesting and most important papers that I have read in 2020. I think considering the impact of mitochondrial dysfunction in humans, not just in the respiratory system, but the potential impact in neuroinflammation. The lot that we don't know about the impact of the environment and infection, in general, to cause adverse health symptoms in us means that publications like this, that show that an antifungal drug can lead to memory preservation and improve memory response in the mice is really just brilliant research. And it emphasizes yet again, that there is a lot in the microbiological arena that we just don't understand and we don't know how it impacts on us. And therefore, all of us need to be very mindful that these hidden microbes that we often don't even think about and take for granted have tremendous long-term impacts on us, not just as a direct infection.
In any case, my name's Dr. Cameron Jones. I'll be back next week and thanks for watching, listening to this podcast, or tuning into this live stream. It will be available on YouTube later. I'll look out for any comments. I'll look forward to responding to those. Stay safe, wherever you are, and I'll see you next week. Bye for now.
Mudarri D, Fisk WJ. Public health and economic impact of dampness and mold [published correction appears in Indoor Air. 2007 Aug;17(4):334]. Indoor Air. 2007;17(3):226-235. doi:10.1111/j.1600-0668.2007.00474.x
Yeo, I.J., Yun, J., Son, D.J. et al. Antifungal drug miconazole ameliorated memory deficits in a mouse model of LPS-induced memory loss through targeting iNOS. Cell Death Dis 11, 623 (2020). https://doi.org/10.1038/s41419-020-2619-5
Pisa D, Alonso R, Carrasco L. Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue. Int J Biol Sci 2020; 16(7):1135-1152. doi:10.7150/ijbs.42257. Available from http://www.ijbs.com/v16p1135.htm
Yang L, Youngblood H, Wu C, Zhang Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener. 2020;9(1):19. Published 2020 Jun 1. doi:10.1186/s40035-020-00197-z
GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
Hamblin MR. Shining light on the head: Photobiomodulation for brain disorders. BBA Clin. 2016;6:113-124. Published 2016 Oct 1. doi:10.1016/j.bbacli.2016.09.002
Fisher MC, Gurr SJ, Cuomo CA, et al. Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture. mBio. 2020;11(3):e00449-20. Published 2020 May 5. doi:10.1128/mBio.00449-20
Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27-37. doi:10.1097/AIA.0b013e318034194e