Recent collaborative research between the University of Helsinki and Aix-Marseille University highlights the potential of exploring the diuretic compound Bumetanide, which has been used in the clinic for more than 50 years to treat various medical problems, including heart, kidney, and liver disease.
Recent preclinical work has shown positive effects of Bumetanide on the underlying causes of various neurological disorders. However, understanding the precise mechanisms through which Bumetanide exerts its therapeutic effects has remained challenging.
While previous studies mainly focused on neurons, recent technological advancements have shed light on the involvement of non-neuronal cells and their interactions in the brain's response to injury.
To investigate the workings of Bumetanide in a specific brain injury model, researchers from the University of Helsinki and Aix-Marseille University employed a combination of techniques, including genetic modifications in animals, measurements of in vivo brain activity, imaging methods, behavioral tests, and cell analysis.
Their findings indicate that Bumetanide helps protect a specific type of brain cell known as parvalbumin-positive interneurons by promoting their interaction with microglia shortly after the injury.
Positive long-term effects
Over time, Bumetanide also influences the behavior of microglia, increasing the production of a protein called Bdnf from these cells. Additionally, it prevents a decrease in the formation of new brain cells in the hippocampus, a region crucial for memory. Treatment with Bumetanide within the first week after the injury resulted in significant improvements in memory and brain activity one month later.
“These findings present a new approach to brain protection through Bumetanide. The compound appears to enhance the positive effects of microglia activation, leading to increased survival of parvalbumin interneurons following the injury”, says Claudio Rivera, Research Director of the Neuroscience Center within Helsinki Institute of Life Science.
According to Rivera, this effect may be attributed to the heightened production of Bdnf by microglia and their increased interaction with interneurons. By preserving these interneurons, Bumetanide may help maintain the balance of gamma-aminobutyric acid (GABA), a vital chemical for normal brain function.
“Moreover, it could contribute to the drug's positive impact on cognitive performance by supporting the generation of new brain cells in adults. Our results offer a fresh perspective on the treatment of various brain pathologies, including traumatic brain injury, stroke, Alzheimer's disease, and developmental disorders”, says Rivera.
Marine Tessier and others, Bumetanide induces post-traumatic microglia–interneuron contact to promote neurogenesis and recovery, Brain, 2023;, awad132, https://doi.org/10.1093/brain/awad132