Fig. 1

Primary and secondary injury cascades following TBI. a Diffuse axonal injury that results from the differential velocities of white and grey matter during a traumatic impact induces tensile strain and microtubule damage within axons. This event induces accumulation of microtubule transport proteins/cargo and calcium influx, resulting in axonal swelling and ultimately axonal degeneration. b TBI reduces cerebral blood flow through impaired autoregulation and increased vasoconstriction, thereby reducing glucose and oxygen throughout the brain. c Axonal stretching induces mechanoporation, facilitating depolarization via the influx of sodium and calcium ions. Additionally, reductions in oxygen and glucose delivery reduce neuronal ATP levels causing failure or reversal of ATP-dependent ion transporters/pumps such as the sodium/potassium ATP pump. This further exacerbates ionic dysregulation by exporting potassium and importing sodium ions. d Ionic imbalances which lead to depolarization of pre-synaptic neurons result in dysregulated glutamate release into the synaptic cleft, which over-activates NMDAR receptors and increases calcium influx into post-synaptic neurons (termed excitotoxicity). e Unregulated calcium influx drives neuronal death through mitochondrial dysfunction and the release of reactive oxygen species (ROS)