Cell Death Mechanisms Following Traumatic Brain Injury

Abstract

Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head-injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post-traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma-induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro- and anti-apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal-regulated kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor-suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

“…1 Previously, the brain was considered to be an immune privileged organ, neither susceptible to nor capable of eliciting an inflammatory response. Nonetheless, it is well established that inflammation represents a common pathological reaction to almost every neurological disease including brain trauma.…”

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…In contusion brain injuries, rapid local brain deformation causes cell shearing and membrane rupture, resulting in irreversible cell injury and necrosis of affected tissues [7,8]. In penumbral regions where cells undergo delayed neurodegeneration, other mechanisms can dominate, including apoptosis, which is a programmed cell death cascade regulated by effector proteins and caspase protease activation [9,10], and autophagy, which is the lysosomal degradation of components within the cell [11][12][13].…”

Neurobehavioral sequelae of traumatic brain injury

“…The primary injury is the immediate insult, whereas the secondary injury is due to the biomolecular and physiological changes that follow the insults. 4 Injury can be focal or diffuse: sudden deceleration or rotational acceleration injury, which generates shearing forces with consequent diffuse axonal injury within the brain, has been implicated as a significant etiology of post-TBI symptoms. 5 Cortical contusion can result in a loss of function served by a given brain area.…”