May 14, 2020
Every year, millions of people around the world suffer brain and spinal cord injuries resulting from trauma, accidents, infections or stroke. These injuries trigger swelling that can lead to death or long-lasting disabilities, but current treatment options are limited and can be risky.
In a new study published in Cell, an international research team reports that a repurposed drug helped reduce swelling and protected against sensory and movement deficits after brain and spinal cord injury in rodent models.
Trifluoperazine (TFP), an antipsychotic already approved for human use, prevented swelling-induced damage by altering the behavior of aquaporins, the membrane proteins that serve as channels for water flow into and out of cells.
The study results could lead to the development of new approaches to treat a wide range of neurological conditions, according to the authors. However, the findings will first need to be replicated in humans.
“This novel treatment offers new hope for patients with central nervous system injuries and has huge therapeutic potential,” said co-first author Mootaz Salman, a postdoctoral research fellow in the lab of Tomas Kirchhausen, HMS professor of cell biology in the Blavatnik Institute at HMS and the Springer Family Professor of Pediatrics at Boston Children’s Hospital.
“Our findings suggest it could be ready for clinical evaluation in the very near future,” Salman said.
The study was led by researchers at Aston University and the University of Birmingham in the United Kingdom.
Brain and spinal cord injuries affect an estimated 75 million people around the world every year. Older individuals have higher risk of sustaining such injuries after strokes or falls, while major causes in younger age groups include traffic accidents and trauma from sports.
After injury, low oxygen levels cause cells in the central nervous system to lose their ability to regulate their internal ionic balance. This allows water to enter through aquaporins, which makes the cells swell, leading to pressure on the skull and spine. The build-up of pressure can damage fragile brain and spinal cord tissues and disrupt the flow of electrical signals between the brain and body.
There is an unmet clinical need for treatments that can stop swelling in the central nervous system before it develops, the authors wrote.
In the current study, the research team took a unique approach to controlling the activity of aquaporins by targeting astrocytes—star-shaped cells in the central nervous system that support neural activity.
After injury, astrocytes dramatically increase the amount of aquaporins in their membranes, which makes cells much more permeable to water. The team found that TFP can block this behavior by preventing a protein called calmodulin from binding to aquaporins, thus reducing swelling.
In preclinical models of brain and spinal cord injury, the research team found that treatment with TFP at the site of trauma allowed rodent subjects to almost fully recover. After two weeks, most treated subjects were indistinguishable from healthy controls on sensory and movement tests.
“This discovery, based on a new understanding of how our cells work at the molecular level, gives injury victims and their doctors hope,” said leader author Roslyn Bill, professor of biotechnology at Aston University. “By using a drug already licensed for human use, we have shown how it is possible to stop the swelling and pressure build up in the central nervous system that is responsible for long-term harm.”
Traditionally, TFP has been used to treat patients with schizophrenia and other mental health conditions. Since TFP is already licensed for use in humans by the U.S. Food and Drug Administration and the UK National Institute for Health and Care Excellence, some barriers would already have been cleared to repurpose it as a treatment for brain injuries if the drug were to prove safe and effective in humans, the authors said.
However, long-term use of TFP is associated with adverse side effects. The researchers stress that further studies to better understand the underlying mechanisms for the drug’s action can help lead to the development of better and safer medicines.
Philip Kitchen, research fellow at Aston University, and Andrea Halsey, graduate student at the University of Birmingham, are co-first authors on the study. Zubair Ahmed, senior lecturer in neuroscience at the University of Birmingham, and Alex Connor, senior lecturer in biomedical sciences at the University of Birmingham, are co-corresponding authors on the study.
The research team also includes scientists from the University of Calgary, Canada;, Lund University, Sweden;, the University of Copenhagen University, Denmark, and the University of Wolverhampton, U.K.
Adapted from an Aston University news release.
Since its founding in 1990, the Harvard Mahoney Neuroscience Institute has helped advance neuroscience at Harvard Medical School by promoting public awareness of the importance of brain research and by helping to fund research at the School's Department of Neurobiology.
Since 1992, the Harvard Mahoney Neuroscience Institute has published On The Brain, a newsletter aiming to educate the public on the latest scientific discoveries about the brain.