Current aspects of pathophysiology and cell dysfunction after severe head injury

Traumatic brain injury is a major health problem in all developed countries . The main aim of this review is to provide a short update on the most rece nt advances in our knowledge of the brain's response to mechanical injuries , focusing on metabolic, cellular, subcellular, and molecular events that t ake place in severe head injuries. Knowledge of these events is essential f or a better understanding of new pharmacological avenues and non-pharmacolo gical strategies, such as moderate hypothermia, which are being developed t o improve the outcome of this silent epidemic. We will focus on several top ics that we consider to be the most significant: diffuse axonal injury, isc hemia and the cascades it generates, metabolic derangements, excitotoxicity , oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed a fter closed head injury are not single events but processes set in motion b y the mechanical impact. These processes are not finished until an unpredic table time after injury. We will discuss recent evidence showing that in di ffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the nonischemic forms of brain hypoxia. The role of exc itotoxicity in mechanically-induced cell death and the molecular events tha t excessive release of glutamate induce, including apoptosis and delayed in flammatory processes, are reviewed. Finally, new knowledge on how central n ervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopatholog y of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.