Secondary injury

Secondary neuronal injury after traumatic brain injury has recently received much attention, with new mechanisms being elucidated and previously described mechanisms being understood better. At a macroscopic level, secondary phenomena include edema, ischemia, necrosis, elevated intracranial pressure, and inadequate cerebral perfusion. At a cellular level, energy failure occurs with a cascade of events that contribute to secondary injury, including elevated levels of intracellular calcium, release of excitatory amino acids, generation of free radicals, and breakdown of the cellular cytoskeleton and membrane with vascular dysfunction eventually leading to cell death ( Fig.,,2).

Fig. 2 Mechanisms of secondary injury: TBI, traumatic brain injury; EAA, excitatory amino acids; NO, nitric oxide.

Excitatory amino acids

The initial event in the sequence is believed to be the release of excitatory amino acids. Glutamate is the most studied of the excitatory amino acids, and the mechanism of injury has been termed excitotoxic injury. Following brain injury, excitatory amino acids are released from injured cells. Glutamate acts postsynaptically at five receptor subtypes which are described on the basis of the agent that specifically activates them. The N-methyl-D-aspartate (NMDA) receptor complex is an ion channel that allows passage of calcium and sodium ions. When activated by glutamate, the NMDA receptor allows calcium ions to enter the cell. Large influxes of calcium ions into neurons stimulate calcium-dependent enzymes with activation of proteases, kinases, phospholipases, and nitric oxide synthase. If unchecked, these processes can eventually lead to cell death with breakdown of the cytoskeleton, free-radical formation, alterations in gene expression and protein synthesis, and membrane dysfunction. Blocking the NMDA receptor improves neuronal survival in vitro and in animal models of neuronal injury. NMDA blockers are currently undergoing clinical trial.

Free radicals

Free-radical formation is an integral aspect of many mechanisms of secondary injury. The most common free radicals studied are superoxide (O 2-), hydrogen peroxide

(H2O2), hydroxyl (OH ), and nitric oxide (NO). Free radicals are atoms or molecules with an unpaired electron in the outer orbit, making them highly reactive. Free iron is an important catalyst of free-radical-mediated injury and is readily available in injured and contused brain tissue. Free radicals damage endothelial cells and injure the brain parenchyma. In so doing, they disrupt the blood-brain barrier and are partly responsible for both vasogenic and cytotoxic edema. Once initiated, free-radical injury is a self-perpetuating process with increasing damage which generates more free radicals. Cells attempt to limit the injury caused by free radicals by binding them with free-radical scavengers such as vitamin E, ascorbic acid, superoxide dismutase, etc. However, these coping mechanisms may be overwhelmed in areas of severe brain injury or ischemia. Pharmacological agents that scavenge free radicals have been effective in reducing neuronal damage in animal models of brain injury. Unfortunately, a human trial of the free-radical scavenger PEG-SOD (polyethylene glycol superoxide dismutase) in severe head injury did not demonstrate an improved outcome.

Nitric oxide

Nitric oxide, a ubiquitous second messenger, has received much attention recently and has been implicated in a variety of cellular processes including vascular relaxation, neurotransmitter effects, and cytotoxicity. It is formed via the conversion of L-arginine to L-citrulline and nitric oxide catalyzed by nitric oxide synthase. The mechanism of nitric oxide cytoxicity is unclear, but it is closely associated with NMDA, calcium, and free-radical-mediated injury. Inhibitors of nitric oxide synthase have been found to reduce neuronal injury in animal models of brain injury. Many other mediators of secondary brain injury are under investigation including catecholamines, adenosine, cytokines, opioid peptides, and thyrotropin-releasing hormone.

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