Researchers at the Medical University of South Carolina provide preclinical evidence that mental losses after a traumatic brain injury can be reversed with complementary inhibition, even when performed two months after the injury.
Credit: Dr. Stephen Tomlinson of Wisconsin Medical School.
Traumatic brain injury (TBI) is a major cause of disability and a risk factor for early dementia. The injury is characterized by a physical insult followed by an acute complement driven neuritis. The supplement, which is part of the innate immune system that works in both the brain and throughout the body, boosts the body’s ability to fight pathogens, boost inflammation and remove damaged cells. The supplement plays a role in the brain, regardless of infection or injury, as it affects 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 determine the role of the complement system in neurodegeneration after a head injury, specifically in the long-term chronic phase of traumatic brain injury. Moreover, the therapeutic management of TBI patients is limited to the acute post-injury phase, as little is known about the link between the initial insult, chronic neurodegeneration and cognitive decline in the following months and years.
Researchers at the Medical University of South Carolina (MUSC), Ralph H. Johnson Medical Center VA and elsewhere report a link between the supplement regimen and the chronic stage of traumatic brain injury. Their results were published online on January 12th The Journal of Neuroscience, Showed that supplement inhibition after 2 months of traumatic brain injury disrupts neurodegeneration and improves cognitive function.
Said Stephen Tomlinson, professor and interim chair of the Department of Microbiology and Immunology, which studies brain injury and the supplementary system.
“The vast majority of the studies that were done to investigate the different treatments in TBI were all conducted using acute treatments, within hours of the initial insult. Our study is important because we started treatment for two months after the traumatic brain injury.”
To fully understand the timing of complementary and chronic traumatic brain injury, Tomlinson’s lab first looked at the body’s response to the affected area. They have shown that certain brain cells, called microglia, destroy synapses that have been tagged with complement in order to degrade. This process reduces the overall number and density of synapses in the brain. Moreover, they reported continuous activation of the supplement for up to three months after the initial insult of a traumatic brain injury, with neuroinflammation expanding across regions of the brain. This inflammatory response promotes synaptic degeneration and was predictive of progressive cognitive decline.
Then the researchers explored the therapeutic effects of blocking the supplement. They used a complement inhibitor that specifically targets sites of supplement activation and injury to brain cells. Inhibitory supplementation stops the decline in brain cell function and reverses mental losses in tasks that assess spatial learning and memory, even when inhibitor delivery is delayed up to two months after injury.
“One of the great advantages of our approach is that we do not systematically discourage integration,” said Tomlinson.
“With acute therapies, it’s not a big problem, but someone’s chronic treatment with a systematically complementing inhibitor is not optimal because the supplement does other important things, from host defense to controlling homeostatic and regenerative mechanisms.”
To date, therapeutic investigations into preclinical models have focused almost exclusively on acute treatments for TBI. With this new insight into the pathology of traumatic brain injury, Tomlinson’s team is suggesting that all stages of injury, including chronic time points, may respond to therapeutic treatments, especially those that involve complementary inhibition.
These results are conclusive, because rehabilitative interventions are the only management strategy available for TBI to improve cognitive and motor functions. Additionally, cumulative evidence shows that rehabilitation is more likely to speed up recovery but not alter outcomes in the long term.
“It gives us a new way to perceive TBI management. Really, the only treatment at the moment is rehabilitative therapy, which is of little use from a clinical point of view. We have found that rehabilitation and supplemental inhibition have additional effects.
Looking ahead, Tomlinson wants to take the translational approach to supplemental inhibition in the chronic phase of TBI even further, beyond that two-month period, and check whether the treatment will continue in mice if it starts from six months to a year. From the initial TBI. Additionally, Tomlinson is developing models of recurrent TBI and plans to investigate anxiety and depression behaviors as well as early dementia, a major concern of veterans, soldiers, and athletes.
Currently, multiple complement inhibitors exist at different stages of clinical development, including those that specifically target sites of injury and disease. Tomlinson himself is the co-founder of a company that investigates targeted supplement inhibition, leading to the possibility of integrating complementary inhibition into the clinic. Thus, studies conducted in Tomlinson’s laboratory could have profound and lasting effects at the clinical level, as supplemental suppression could ultimately help thousands of patients with TBI each year.
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