March 1, 2024

Novel Drug May Offer Protection for the Brain Against Repeat Concussions

A new study has revealed that a novel drug could potentially protect the brain from damage after repeat concussions, also known as repetitive mild traumatic brain injury (TBI). These repeat concussions can increase the risk of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. However, the research also suggests that some individuals who experience repetitive mild TBI never develop these major diseases.

The study, published in the journal PNAS Nexus, focused on investigating the role of a protein called p17 in safeguarding the brain against long-term pathologies. The researchers discovered that p17 initiates the production of C18-Ceramide, a bioactive sphingolipid, in stressed neurons. This sphingolipid acts as a marker for damaged mitochondria in neuronal axons.

The labeled mitochondria are then identified and removed by autophagosomes, which are specialized structures responsible for breaking down and recycling cellular components. To further understand the protein’s significance, the scientists conducted experiments on mice. They disrupted the p17 protein in some of the mice and exposed them to a repetitive less-than-mild closed-head injury paradigm.

After three months, the p17-knockout mice exhibited significant sensorimotor deficits, which further progressed to cognitive deficits by six months. In contrast, the control mice showed no impairments in their behavior. The researchers examined the brains of the p17-knockout mice that had undergone repetitive concussive brain injury. They discovered compromised and disarranged membranes in the axonal mitochondria, which would typically be destroyed in normal mice.

However, since the process of destroying the dysfunctional organelles was interrupted due to the absence of p17, these damaged mitochondria continued to exist. This led to axonal degeneration, a significant contributor to the pathological outcomes observed in the mice. To address this issue, the researchers developed a drug called LCL768, which specifically targets damaged mitochondria in a process known as mitochondrial targeting.

When administered to mice, LCL768 prevented the development of secondary axonal degeneration and resulted in improved functional outcomes compared to the placebo group. The drug accumulates in the damaged mitochondria and helps restore the process by which these organelles are removed. The researchers also studied human tissue samples from individuals with a history of repetitive traumatic brain injury, along with verified cases of CTE.

The samples from those with CTE showed reduced expression of p17 and fewer mitochondrial C18-Ceramides compared to healthy control samples. Based on the findings, the authors suggest that drugs promoting a healthy pool of axonal mitochondria in the brain could serve as potential prophylactic treatments after a concussion.

In conclusion, this study highlights the potential of a novel drug, LCL768, in protecting the brain against the damaging effects of repeat concussions. By targeting damaged mitochondria, the drug may help prevent the development of secondary axonal degeneration and improve functional outcomes. Further research is needed to fully understand the efficacy and safety of this drug, but it holds promise for future therapeutic interventions in individuals at risk of chronic traumatic encephalopathy and Alzheimer’s disease.

1. Source: Coherent Market Insights, Public sources, Desk research
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