The concept that release of excitatory amino acids (EAA) may produce pathological changes in the brain is now well established. Such """"""""excitotoxicity"""""""" appears to be related to a number of neurological disorders affecting the brain. These include ischemia-related disorders such as stroke, as well as consequences of traumatic injury to the brain. EAA are extremely important in the normal function of the spinal cord but there is currently little information on the role of excitotoxicity in spinal cord disorders. The recent report of reduced functional deficit when the NMDA receptor antagonist MK-801 was administered shortly after a standardized traumatic spinal cord injury suggests the hypothesis that excitotoxicity may play a role in spinal cord injury. We propose to test this hypothesis. Using a standardized, reproducible model of graded spinal cord contusive injury in the rat, we will examine the effects of several individual and combinations of EAA antagonists administered at the time of injury. We will compare experimental and control groups with respect to the functional deficits and histopathological lesions resulting from contusion, as well as the distribution of EAA receptors. We will then examine the time period during which EAA antagonists are effective in altering the consequences of contusive injury to determine a potential window of opportunity for therapeutic intervention. Using autoradiographic techniques, we will examine the distribution of EAA receptors in the spinal cord before and after contusion to determine which regions of high EAA receptor density are preferentially affected by contusion. Microdialysis will be used to measure EAA levels after contusive injury. We will also determine whether the application of exogenous excitotoxins to the spinal cord mimics some of the behavioral and morphological characteristics of contusive injury and/or can exacerbate the consequences of very mild contusive injuries. The results of these studies should provide basic information about the mechanisms involved in traumatic spinal cord injury and a potential effective approach.
Showing the most recent 10 out of 108 publications
