Affiliations: Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Box 631, MCV Station, Richmond, VA 23298-0631, USA
Note: [] Tel: + 1-804-8289165.
Abstract: Secondary brain injury is a well-demonstrated contributor to the morbidity and mortality of severe head injury. At least ten new compounds which antagonize the effects of glutamate in the brain are currently undergoing clinical evaluation as putative protectants against this secondary injury. None have yet shown clear benefit in humans. It is accepted that excitatory amino acids, glutamate in particular, have ‘neurotoxic’ effects on the brain, especially when present in excessive amounts. Whether or not this excitatory amino acid toxicity represents the major pathway for secondary damage is disputed. In the laboratory, over 300 studies have now demonstrated the ability of glutamate antagonist drugs of various types to prevent ischemic and post-traumatic acute brain damage. The magnitude and consistency of protection afforded by this group of compounds exceeds that which has ever been shown with any other mechanisms. Laboratory studies using in vitro neuronal models have implicated glutamate as a promoter of ionic flux and calcium entry across the cell membrane, which may then initiate astrocytic swelling and neuronal necrosis. In vivo animal models of brain trauma and ischemia have demonstrated glutamate release and potassium efflux into the extracellular fluid (ECF). Outcome in these models is improved, as assessed by both histopathology and behavioral studies, when glutamate antagonists are used. Additionally, presynaptic glutamate blockade in animal models such as middle cerebral artery (MCA) occlusion and subdural hematoma, creates reduction in lesion size which is paralleled by reduced glutamate production. In bridging the gap between the laboratory and the patient care setting, human microdialysis studies have shown massive release of excitatory amino acids into the ECF after severe head injury. Early studies with TV-methyl-D-aspartate (NMDA) antagonists in head injured humans have demonstrated a reduction of intracranial pressure and an improvement in cerebral perfusion. Future studies are needed to examine further the value of protection from excitatory amino acid induced injury.
