Traumatic Brain Injury (TBI) affects approximately 270,000 people a year and costs the U.S. more than $48 billion annually. Around 70,000 people die each year from head injuries, but many of those who survive are left with long-term disabilities as a result of their injuries. While there have been many promising therapeutic treatments for TBI, clinical trials have not been successful. In vitro studies can provide insight into the cellular mechanisms leading to neuronal death and degeneration after TBI and aid in developing more effective treatments.

The goal of this work was to investigate the mechanisms and pathways by which damage to neurons progresses in the context of Traumatic Brain Injuries by characterizing the behavior and response of cells to individual components of the proposed TBI mechanisms – specifically;​ membrane damage, increases in intracellular calcium, mitochondrial damage, and oxidative stress and lipid peroxidation. A clear understanding of the injury mechanisms and pathways is a requirement for the development of successful therapeutic interventions after injury.

The mechanisms for cell death and dysfunction after TBI are hypothesized to be initiated by damage to the plasma membrane, which results in a loss of ionic homeostasis. Calcium flows into the cell and causes an activation of various proteases that disrupt the cytoskeleton and cause deficits in axonal transport. Mitochondria, the primary source of cellular energy, also work in the cell as calcium buffers, but become dysfunctional when they cannot accommodate the excess calcium and result in the release of stored calcium. Damage to mitochondria results in an inability to produce ATP, whereby the cell starves, ATP-driven motors will be arrested, and ATP-driven ion pumps can no longer work to restore ion homeostasis. Damage to the mitochondria can also result in the opening of the mitochondrial permeability pore (MPP) and an increase in oxidative stress. Free radicals can further damage the mitochondria and the plasma membrane, and thus propagate and prolong cellular dysfunction. Damage to the mitochondria and the opening of the MPP also serves to release sequestered calcium from the mitochondria into the cytoplasm. These insults culminate in axonal “beads” and neuronal dysfunction and death.