Brain injury and repair mechanisms: the potential for pharmacologic therapy in closed-head trauma

Rotational acceleration from closed-head trauma produces shear-strain brain injury at the interface of gray and white matter. The initial injury is followed by progressive damage involving three key phenomena: progression of subtle focal axonal damage to axonal transection between six and 12 hours after injury, progressive development of tissue microhemorrhages between 12 and 96 hours after injury, and development of tissue and cerebral spinal fluid lactic acidosis that does not appear to be explained by trauma-induced tissue depolarization, activation of phospholipases and the release of free arachidonic acid, radical generation by metabolism of arachidonate, and lipid peroxidation with consequent membrane degradation and partial mitochondrial uncoupling. Because of terminal differentiation, neurons may have a limited membrane repair capability that might be stimulated by growth factors. Other potential therapeutic interventions include calmodulin inhibitors, iron chelators, and free radical scavengers.