IMAGE: Slices of the hippocampus from an uninjured brain (upper part) or a brain three months after TBI (lower part). There is an increase in astrocytes (green) after a brain injury. to view most
Credit: Dr. Stephen Tomlinson of Medical College of Wisconsin.
Head trauma (TBI) is a major cause of disability and a risk factor for early-onset dementia. The injury is characterized by a physical insult followed acutely by complement-driven neuroinflammation. Complement, a part of the innate immune system that works in the brain and throughout the body, increases the body’s ability to fight pathogens, promote inflammation and eliminate damaged cells. Complement plays a role in the brain, regardless of infection or injury, as it influences brain development and synapse formation. In TBI, complement-induced inflammation partially determines the outcome in the weeks immediately following the injury. However, more research is needed to define the role of the complement system in neurodegeneration after traumatic brain injury, specifically in the long-term chronic phase of TBI. In addition, the therapeutic management of patients with TBI is limited to the acute phase after the injury, as little is known about the link between the initial insult and chronic neurodegeneration and cognitive decline in the months and years that follow.
Researchers at the Medical University of South Carolina (MUSC), Ralph H. Johnson VA Medical Center and elsewhere have reported a link between the complement system and the chronic phase of TBI. Their results, published online on January 12 at Journal of Neuroscience, showed that complement inhibition two months after TBI interrupts neurodegeneration and improves cognitive function.
“TBI is associated with cognitive decline and dementia, and there is no pharmacological treatment to prevent that cognitive decline,” said Stephen Tomlinson, Ph.D., professor and acting chairman of the Department of Microbiology and Immunology, who studies brain damage and the complement system.
“The vast majority of studies that investigated different therapies in TBI were all done with acute treatments, a few hours after the initial insult. Our study is significant because we are starting treatments two months after TBI.”
To more fully understand complement time and chronic TBI, Tomlinson Lab first looked at the body’s response to the damaged area. They showed that certain brain cells, called microglia, destroy neuronal synapses that have been marked by the complement for degradation. This process reduces the overall number and density of synapses in the brain. In addition, they reported continuous complement activation until three months after an initial TBI insult, with expansion of neuroinflammation in the brain regions. This inflammatory response promotes degeneration of synapses and was predictive of progressive cognitive decline.
The researchers then explored the therapeutic effects of complement block. They used a complement inhibitor that specifically targets complement activation sites and brain cell damage. Complement inhibition stopped the decline in brain cell function and reversed mental losses in tasks that assess spatial learning and memory, even when the administration of the inhibitor was delayed until two months after the injury.
“A major advantage of our approach is that we do not systematically inhibit complement,” said Tomlinson.
“With acute treatments, it is not such a problem, but treating someone chronically with a complement inhibitor systemically is not ideal because the complement does other important things, ranging from the defense of the host to the control of homeostatic and regenerative mechanisms. “
So far, therapeutic investigations in preclinical models have focused almost entirely on acute treatments for TBI. With this new view on TBI pathology, Tomlinson’s team suggests that all stages of the injury, including chronic time points, can respond to therapeutic treatments, specifically those that involve complement inhibition.
These findings are critical, as rehabilitation interventions are the only treatment strategy available for TBI to improve cognitive and motor functions. In addition, cumulative evidence shows that rehabilitation is likely to accelerate recovery, but does not alter long-term outcomes.
“This gives us a new way to understand the management of TBI. In fact, the only therapy at the moment is rehabilitation therapy, which clinically has very little benefit. We found that rehabilitation and complement inhibition have additive effects,” he said. Tomlinson.
Looking to the future, Tomlinson wants to take the translational approach to complement inhibition in the chronic phase of TBI further, beyond the two-month window, and is investigating whether the treatment will still work in mice if it starts in six months to a year from now. Initial TBI. In addition, Tomlinson is developing repetitive TBI models and plans to investigate anxiety and depression behaviors, as well as early-onset dementia, a significant concern for veterans, soldiers and athletes.
Currently, several complement inhibitors are in various stages of clinical development, including those that are specifically targeted to sites of injury and disease. Tomlinson himself is a co-founder of a company that is investigating targeted complement inhibition, leading to the potential for incorporating complement inhibition into the clinic. Thus, studies carried out in Tomlinson’s laboratory could have profound and lasting impacts at the clinical level, where complement inhibition could eventually help the thousands of patients suffering from TBI each year.
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About MUSC
Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the only integrated academic center for health sciences with the sole responsibility of serving the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and 700 residents in six faculties: Dentistry, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state’s leader in obtaining funds for biomedical research, in fiscal 2018, MUSC set a new record, raising more than $ 276.5 million. For information on academic programs, visit http: // musc.
Like the medical health system at Medical University of South Carolina, Health MUSC is dedicated to providing the highest quality patient care available, while training generations of competent and compassionate healthcare providers to serve the people of South Carolina and beyond. Comprised of approximately 1,600 beds, over 100 extension sites, MUSC College of Medicine, the doctors’ practice plan and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals located in Charleston, Chester, Florence counties , Lancaster and Marion. In 2019, for the fifth consecutive year, US News & World Report named MUSC Health as South Carolina’s # 1 hospital. To learn more about clinical patient services, visit http: // muschealth.