According to research developed by researchers ANSTOinvolved in an international study, the long-term use of anxiolytic drugs could lead to a cognitive impairment in vulnerable individuals.
The result of the Research have been published in the scientific journal Nature Neuroscience.
Long-term use of anxiolytic drugs – here’s what effect they have on the brain
The study was critically based on a unique laboratory model developed at ANSTO known as “Kockout Guwiyang Wurra -TSPO” (A healthy mouse that lacks an ancient evolutionary protein normally found in mitochondria, the organelle that supplies energy to a cell. Due to the importance of the protein for energy generation, its name in the Dharawal language is Guwiyang Wurra “mouse of fire”).
The study suggested that the anxiolytic drugs did not act directly on nerve cells but on microglial cellsthat is cells of the intrinsic immune system of the brain that can collect around nerve cells and their connections, the synapses, and that the movement of microglial cells has interfered with the dendritic spines (small protrusions from the neurons at the tip of which are the connections synaptic to other nerve cells): “This observation is important because long-term use of anxiolytic drugs is believed to contribute to an acceleration of dementia and how this could occur was not known.“, Stated the co-author of ANSTO, the Proffessor Richard Banati.
“The knowledge gained in this work by a large international team helps in the development of anxiolytic drugs without such damaging cognitive effects. The specific experiment looked closely at how long-term use of anxiolytic drugs, such as diazepam, can alter the complex wiring of the brain. We have neurons and each neuron connects to another neuron by what is called a synapse. Here, the research team recognized the importance of other neighboring cells, the microglial cells “Banati continued.
“These are small, highly mobile cells that are part of the non-neuronal matrix in which nerve cells are embedded. This matrix makes up a substantial part of the brain and is actually directly affecting the functioning of neural networks. The compound that was studied, diazepam, did not go directly to the long spines and synaptic connections between the nerve cell itself, but to the microglia.“.
“In doing so, the drug changed the normal activity of the microglial cells and indirectly the maintenance function that the microglia has around the synaptic nerve cell connections. It is interesting to see how the local immune system of the brain, which includes microglial cells, directly participates in the overall functional integrity of the brain.“.
“There are a number of serious diseases, such as dementia, but in particular also those characterized by often extreme or prolonged fatigue, as we now see in” long covid “or after accidental or therapeutic exposure to radiation, where we know that the system immune responds very strongly“.
“If the connections between neurons are disrupted by the activity of microglial cells, then it is almost like disconnecting neural connections, and this would explain how very subtle changes could drive further progression of dementia or, more speculatively, cause severe fatigue. . The conceptual meaning of the work for me is that it shows us that we may want to see the brain not just as a telephone switchboard with point-to-point connections, but as a switchboard in an unusual environment.“.
The collective movement of microglial cells can be thought of as similar to what happens in lava lamps. Microglial cells create an amorphous but still locally confined dynamic, like bubbles that rise and then fall when pushed by heat. This ever-changing and localized activity can interfere with more static cable connections, in extreme cases, perhaps comparable to small local cable fusions affecting the entire system that otherwise seems fine.
The overlap of the immune system (glial cells) and the nervous system (neurons) is critical to understanding the underlying cellular mechanism. Both systems mediate between the internal world of the organism and input from the environment. This self / non-self interaction manifests itself in a dynamic equilibrium in which the connections are formed by the nervous system and modulated or even interrupted by the cells of the immune system.
“The use of the potent TSPO knockout mouse model provided evidence that the mitochondrial protein TSPO was involved in the remodeling of dendritic connections by microglial cells. Anxiolytic drugs, such as diazepam, bind to the TSPO. In a genetically modified animal such as a TSPO “knockout mouse, the side effects described for diazepam simply do not occur. Diazepam, which was administered to laboratory models, showed a reduction in dendrite spines, while these defects did not occur in the TSPO knockout model “explained Professor Banati.
Based on the results, the authors concluded that, as a consequence of the use of anxiolytic drugs (benzodiazepines), the loss of dedriditic spines from TSPO accelerated cognitive decline.. It was also considered possible that chronic use of anxiolytic drugs such as benzodiazepines altered the function of microglial cells, which could promote specific pathological changes in the brain system.
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