Video & transcript. This research is important because it is telling us how dangerous diazepam (Valium) and its drug family (the benzodiazepines - like Xanax and Serepax, and temazepam etc) are. Speaking as a mental health professional, I can say that people have known for a long time that benzodiazepines cause enormous harm to many people who take them. It is, however, extremely difficult to get this message out because of the power of the drug lobby. It is also almost impossible to get doctors to stop prescribing them, in part because patients to keep coming back for more, thus boosting the size of their practices, but also because addiction makes it almost impossible for those patients to do without these prescription drugs. Apart from the terrible effects of addiction, which causes the use of these drugs to toxic levels, with obvious side-effects like epileptic seizures, over-sedation and death, especially when mixed with other drugs/alcohol, it was hard to isolate. Was the intelligence of people who used diazepam fundamentally at risk or were we just looking at the effects of sedation and other 'life-style' problems? The report below says unequivocally that benzodiazepines exacerbate and probably cause dementia. Readers may know benzodiazepines under many different names. There is an argument that benzodiazepines should only be prescribed to prevent status epilepsy, which is life-threatening. To underline the dangers of regular benzodiazepine use, especially in epilepsy, benzodiazepine withdrawal can also cause status epilepsy. I wondered should I headline this with benzos as 'causing' or 'exacerbating' dementia, then decided that, if they exacerbate it, they also become a cause of it. Another problem is, of course, that there are many different kinds of dementia.
ANSTO & Australian Government research report, "Does long-term anti-anxiety medication rewire the brain?"
Transcript from video: "Professor Richard Banati explains how long-term anti-anxiety drugs use effects the brain."
The significance of the work is that it addresses a very important problem. Patients, who have developed cognitive deficits, memory loss, are also very often in a state of high anxiety, and then they are treated with anxiolytics, medication which reduces the state of anxiety and makes it bearable. And the classical pharmaceutical that is used is diazepam [Valium], and over time it was observed that, while the anxiety is controlled by diazepam, the cognitive deficit gets worse. And that paper, that piece of work, that included an international group, found a cellular mechanism. A cellular mechanism that explains how the progression of dementia occurs or is accelerated potentially by these anxiolytics. That gives us now a basis to develop anxiolytics that do not have this long-term undesirable effect. The specific experiment looked into the wiring of the brain. So we have the neurons and the neuron connects to another neuron by what is called a synapse. But what they realized is that, next to the synapse, are other cells - if you wish the Matrix or the glue - and it makes up a substantial part of the brain. And the compound, in this case, diazepam, actually didn't go to the nerve cell itself, but to the glial or, that is ‘glue cells’ around it. And that is a mechanism that is unexpected because it means that the integrity of the nervous system - that network of neurons - is actually also determined by the state of this matrix that accumulation of other cells around the synaptic connectivity - this connection. And what happens is [that] the connections are sometimes severed by these cells and then it's almost like unplugging the connection and that would explain why, without very obvious pathology, subtle changes can drive a further progression of dementia.
Earlier on, you asked me, ‘What's the significance of that work?’ And, for me personally, the significance is that it shows us that we might want to look at the brain, not only as a switchboard - one point to point connection to another - but as the switchboard with lava lamp characteristics, or a lava lamp is something that creeps up. It’s definable, but it's not a point-to-point communication, if you wish. It goes up and down and these glial cells that I mentioned earlier, this matrix cell does in fact respond to pharmaceuticals like diazepam. And then, its sort of creeping motion that it uses to regulate the number of connections, is influenced by medications - almost like the hand in the switchboard that unplugs and plugs back. And that's more a form of - I would call it ‘amorphous computing.’ It's not quite as mechanistic point to point, as we have sort of learned to think about the brain. It's the interplay between the determined point to point and the creeping effects that come from that matrix, if you wish, [that] determine the overall outcome. Like for example, memory loss, or how that is being compensated.
And to know that a drug like diazepam, that was really developed to target neurons, has its effect through other non-neuronal cells, that's a real breakthrough.
And these other cells, in our specific case, these are cells that are called microglia – small glue cells. If you translate that, these cells belong to the immune system. And now we have two systems interacting: the nervous system, which is cell non-cell, and the immune system, which is also cell and non-cell. So I think there's a higher-order meaningfulness that these two systems overlap. And what they do together is [that] they regulate the density of synaptic connections, and they do these in - one would call that - a dynamic equilibrium.
So, connections are made and connections are severed. And if that turnover is changed, then we get dementia, or other states of loss.
I might become a little bit technical now. There's a protein called TSPO (Translocator Protein), and it was actually discovered decades ago when people realized that diazepam binds to something else, and that something else turned out to be the TSPO.
The TSPO is found exclusively on mitochondria. Mitochondria [are] the small organelles in the cell that produce the energy for the cell and regulate all sorts of other cellular responses, like motility, meaning the ability to move, the ability to produce hormones and so on. So, they are really deeply embedded in the system of regulation. What the team that we have been part of found is, if that protein, this TSPO is not present in a genetically modified animal like a Knockout Mouse, then the side effects that are described for the diazepam, simply do not occur. And that really very much points to the crucial role of this small protein, the TSPO.
And to use an analogy, the TSPO is always regulated when there is stress on the cell. The cell has to work. And then it is in the outer shell of mitochondria, like a rivet in a ship that has a lot of load to carry, and then the number of rivets goes up. And we don't exactly know what the TSPO does, but I think it has a regulatory role in energy metabolism. And that is perhaps where our work at ANSTO comes in, because at ANSTO we are very much interested in understanding fundamental reactions of life, and that the organelle of the mitochondria is one of the most fundamental, like the cell nucleus parts of a cell. And, of course, we are interested in this because we are dealing with radiation, and life is adapted to radiation, and how has it done that?
The TSPO is three billion years old. On that little note alone, it's very important. It's a very important generic mechanism of adaptation to all sorts of stresses. And that's why we have chosen it here at ANSTO to pursue in all sorts of contexts: Clinically, as I said, in dementia, but also in radiation adaptation. Cancer therapy, you name it. You'll find it in all those conditions where the cell has to respond to an external stressor.
Press release from ANSTO and the Australian Government regarding Diazepam as probably causing dementia and or making it worse
The text below was sent to us along with the video:
Often patients with cognitive loss experience anxiety, which is treated with anti-anxiety medicines. The challenge is that long-term use of anti-anxiety medicines may further increases cognitive deficits.
The biological mechanism of these undesirable, long-term effects has been unknown, but now new research by an international team of scientists has shed some light on the problem.
Using a unique genetic model, a gene knock-out, developed by ANSTO, they have new understanding about how some anti-anxiety medications act on both nerve cells and the brain’s own innate immune cells, called microglia cells.
Here’s what the research suggests is happening:
Synapses are the connection points by which nerve cells in a brain form a functioning network, supporting everything from regulation of organs to higher level thinking.
It is known that when the normal turn-over of synapses is disturbed, cognitive loss can accelerate - as has been observed in patients with dementia.
What has been largely ignored in research to date, are the cells surrounding the synapses. They have long been dismissed as little more than glue, hence their Greek name for glue: glia.
A subgroup of those glia cells, called microglia cells, are known to be part of the brain’s own local innate immune system and are apparently involved brain structures changing (either as part of normal brain development or in the instances of brain disease).
What the team of scientists discovered is that some anti-anxiety drugs exert unexpected ‘off-target’ effects on these microglia cells, causing them to behave differently.
ANSTO’s Professor Richard Banati explained that the research has significant implications for dementia patients experiencing anxiety and will potentially help pave the way for better treatments.
“What we now have is experimental evidence that certain anti-anxiety drugs can interfere with microglia and thereby reduce the normal formation of synapses between nerve cells, essentially resulting in an increased ‘unplugging’ in the neural network and thus loss of its functional integrity,” Professor Banati said.
“The study highlights a very important problem, as often patients with cognitive loss experience high levels of anxiety and are treated with some of these drugs.
“The finding is important because it may help us to understand how the progression of dementia occurs or is potentially accelerated by some of the classical anti-anxiety drugs.
“And practically, it is useful because it will provide a foundation for further research into the development of anti-anxiety drugs which do not have these long-term, undesirable effects.”
Professor Banati said in addition to the ‘off-target’ effects of anti-anxiety medicines, the study offers new insights into the close relationship of synapses with surrounding cells and how this may affect brain functions in a wider range of brain diseases.
“Conceptually, scientists often compare the brain and its network formed by nerve cells to a telephone switchboard with relatively stable point-to-point connections, which ignores that the brain also undergoes slow and subtle, but continual structural changes,” he said.
“In contrast to the network of nerve cells, the collective motions of microglial cells seem more comparable to what occurs in lava lamps - with locally confined dynamics in form of moving bubbles that change with the amount and gradient of heat.
“This ever-shifting, localised activity can interfere with the more static wire connections, in extreme cases directly affecting the connection points and resulting in small, local and often difficult to detect “cable melts” that can disable a whole network, which otherwise looks fine.
“The research revealed a dynamic equilibrium in which connections are formed between nerve cells and changed, or even severed, with the active participation of cells of the innate immune system.”
While ANSTO and the Lucas Heights reactor are best known for the manufacture of nuclear medicine, its scientists and equipment are also highly involved in medical research.
ANSTO’s work involved molecular biology, high resolution microscopy and in the foundational, previous work, brain imaging for the detection of active microglia in the living brain using selective radioligands.
International collaborators included Ludwig Maximilian University of Munich, German Centre for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, University Hospital of Munich, Shanghai Institute of Organic Chemistry, Brain and Mind Centre the University of Sydney, University of Regensburg, University of Illinois at Urbana-Champaign, University of Zurich, Swiss Federal Institute of Technology, and the Technical University Munich.
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