The Pathobiology of Traumatic Brain Injury

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Abstract
The recent appreciation that traumatic brain injury is a dynamic process, initiated at the time of injury but not concluded for hours to days afterward, has resulted in the expectation that treatments can be designed to interrupt the processes that result in delayed cellular dysfunction and, thus, can decrease the amount of traumatic brain damage. Thus, for the first time, treatments specific for brain damage are envisioned. These can provide a fundamentally different approach to the treatment of the damaged brain than currently used treatments that deal with epiphenomena of traumatic injury, such as increased intracranial pressure or secondary ischemia. The processes that result in delayed cellular damage may be initiated by transient ionic fluxes induced by traumatic, temporary holes in the cell membrane lipid bilayer (mechanoporation). Resulting changes in intracellular ionic composition, if uncorrected, result in 1) traumatic depolarization with resultant neurotransmitter release, postsynaptic receptor dysfunction, and excitability changes; 2) calcium-mediated activation of proteases and phospholipases, with resultant cytoskeletal protein dissolution and free radical-induced lipid peroxidation; 3) inflammatory processes that elicit tissue-damaging cytokines; and 4) immediate and delayed activation of numerous genes with a resultant production of a panoply of new proteins. The future challenge to neurotrauma investigators is to better understand these processes and to develop interventions that will halt them before permanent brain damage occurs.