Traumatic brain injuries (TBIs) can occur in different ways, such as from a blast explosion or a blunt force impact like hitting your head in a fall or accident. The way these injuries affect the brain is different. Research suggests that even a single blast exposure can lead to long-term brain damage, but scientists still don’t fully understand how this happens, and current treatments mostly focus on relieving symptoms.
This image shows brain cells before and after blast exposure. Blue marks cell nuclei, and red highlights PAR protein activity. The merged images show where both appear together. White arrows point to cells with PAR activity, comparing normal and blast-exposed cells after 24 hours. Credit: Krishnan Muthaiah, Vijaya Prakash, et al./Immunity, Inflammation, and Disease
One key factor in brain damage from blasts is an enzyme called PARP1 (Poly ADP-ribose polymerase-1), which plays a role in cell damage and inflammation. When over-activated, PARP1 uses up important molecules called NAD+ and ATP, which are essential for energy production and cell repair. This overuse can worsen oxidative stress, a harmful condition that damages brain cells.
Vijaya Prakash Krishnan Muthaiah, Ph.D., a 2019 Emerging Research Grant scientist, and team previously conducted research that showed PARP1 becomes overactive after a blast injury, affecting certain brain cells—astrocytes and microglia—differently. They hypothesized that blocking PARP1 may help reduce oxidative stress, an imbalance in the brain that causes damage.
Their new study, whose results appeared in the journal Immunity, Inflammation, and Disease in January 2025, focuses on the role of the PARP1-SIRT-NRF2 pathway, a chain reaction in brain cells that influences inflammation and oxidative stress after a blast injury.
The goal was to understand how PARP1 activation after a blast affects brain cells, particularly how it changes energy levels (ATP) and antioxidant defense mechanisms in astrocytes and microglia, two types of brain support cells.
Since NAD+ is shared by both PARP1 and sirtuins, a group of proteins involved in cell survival and stress response, the study found that after a blast, important protective proteins (SIRT1, SIRT3, and NRF2) were reduced, meaning the brain’s ability to fight oxidative stress was weakened.
ATP levels increased but most of this energy came from glycolysis, a process linked to inflammation, rather than oxidative phosphorylation, which is the brain’s more efficient way of producing energy. This shift suggests that inflammation is triggered after a blast injury and plays a significant role in brain cell damage.
The findings suggest that blast injuries cause excessive activation of PARP1, which disrupts the brain’s natural ability to manage stress and inflammation. This reduces the activity of sirtuins, which help regulate cell repair and stress responses, and leads to an imbalance in antioxidants, making brain cells more vulnerable to damage. These insights could help scientists develop better treatments to protect the brain after blast-related injuries.
This is adapted from the abstract of the paper in Immunity, Inflammation, and Disease. Vijaya Prakash Krishnan Muthaiah, Ph.D., is an assistant professor in the department of rehabilitation science at the University at Buffalo. His 2019 Emerging Research Grant was generously funded by Royal Arch Research Assistance.
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The findings suggest that blast injuries cause excessive activation of PARP1, which disrupts the brain’s natural ability to manage stress and inflammation. This reduces the activity of sirtuins, which help regulate cell repair and stress responses.