Pharmacological studies have shown that blockade of glutamate receptors and its release in models of focal and global cerebral ischemia, and shear injury (such as fluid percussion), have shown larger and more consistent neuroprotective efficacy than any other mechanism tested thus far. Clinical trials with glutamate antagonists are now in progress for severe head trauma. Nevertheless, the role of glutamate in the pathophysiology of both cerebral ischemia and shear injury, remains poorly understood. In contrast to other pathophysiological mechanisms, the presence of glutamate can be demonstrated during acute ischemia and after shearing injury, and its electrophysiological and metabolic effects upon cerebral tissue may be demonstrated. A central paradox however, remains: the levels of glutamate demonstrated in animal models and also in human microdialysis studies after head injury, are at least one order of magnitude lower than the concentrations needed to damage the intact cortex in the rat. This discrepancy exists even when allowances are made for microdialysis probe recovery efficiencies, and tortuosity factors in the extracellular space. It is therefore necessary to postulate that other mechanisms must act synergistically together with glutamate, in order to magnify its neurotoxic effects in both ischemia, and shearing injury. The purposes of this subproject is thus to apply new in vivo models of 'pure' glutamate neurotoxicity to trauma, and to test for factors which exacerbate or ameliorate the neurotoxic effects of glutamate in trauma and ischemia. The utility of the model as a potential 'screening tool ' for drugs and drug combination will be evaluated. New drugs and combinations shown to be efficacious in this model, can then go forward for behavioral and histological evaluation in models of fluid percussion, weight drop, and focal and global ischemia.

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National Institute of Neurological Disorders and Stroke (NINDS)
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