Quite the opposite of the gift that keeps on giving, a traumatic brain injury (TBI) can have varied and progressively negative consequences. Beyond short- and medium-term problems with memory, cognition and mental health, sufferers of TBI are more likely to develop chronic neurodegeneration. They are also at higher risk of developing more severe neurodegenerative diseases such as Alzheimer's and Parkinson’s sooner than others – though why and how has not been fully clear to scientists.
Now, a team at Harrington Discovery Institute at University Hospitals has published research in Cell Reports Medicine that offers insight into the nature of TBIs, making encouraging headway toward therapeutic options to help patients avoid related chronic health challenges.
The study was led by Andrew A. Pieper, MD, PhD, Director of the Harrington Discovery Institute Brain Health Medicines Center and Morley-Mather Chair in Neuropsychiatry, UH Cleveland Medical Center; and Xin Qi, PhD, Jeanette M. and Joseph S. Silber Professor of Brain Sciences, Case Western Reserve University. Their team focused on how parts of brain cells called mitochondria work after a TBI, taking note of changes in the mitochondria’s essential processes, fission and fusion.
Two cellular proteins, Fis1 and Drp1, govern these processes to help keep cells healthy, balancing energy and removing damaged parts. Previous studies have linked elevated Drp1 to maladies such as Alzheimer’s and Huntington’s disease. By contrast, Dr. Pieper and Dr. Qi’s team discovered that after TBIs, elevated levels of Fis1 create energy imbalances that lead to the same kind of long-term neurodegeneration caused by elevated Drp1 in other conditions.
“Our findings indicate that targeting this imbalance early can protect against long-term cognitive decline after TBI,” said Dr. Pieper.
By administering P110, a novel drug that Dr. Qi previously developed with the support of Harrington Discovery Institute, the team was able to block the harmful effects of the altered interaction between the two proteins after TBIs. Giving the drug soon after the incident for just two weeks permanently normalized mitochondrial activity, preserved brain function, and prevented long-term damage. The researchers say these results could amount to decades of quality of life for TBI patients.
“This is the first time anyone has shown that a short treatment after a brain injury can stop long-term damage," said Dr. Pieper.
The breakthrough highlights the potential for clinical trials of P110 or similar compounds in TBI patients, eventually filling the current gap in treatment options for stopping this acute injury from turning into a lifelong ailment.
“We anticipate that the model will continue to yield insights into the pathophysiology of TBI and open new avenues for therapeutic development,” said Dr. Qi. “This research not only offers hope for TBI patients, but it also provides a validated model for studying chronic neurodegeneration after TBI.”
For more information about this groundbreaking work, please refer to Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury in Cell Reports Medicine.
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Neuroscience
University Hospitals - Cleveland
Harrington Investigators
