EXCITOTOXIC MECHANISMS IN POST TRAUMATIC NEURONAL DEATH

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The long range objectives of this research are to identify cellular mechanisms responsible for the death of selectively vulnerable neuronal populations following head injury in order to identify treatments which may prevent the development of debilitating neurological deficits. The role of excitatory amino acid toxicity (excitotoxicity) in degenerative processes which occur as a consequence of two components of concussive brain injury, mechanical cortical injury and partial ischemia due to raised intracranial pressure (ICP), will be examined separately and in combination using in vivo animal (rat) models. We will examined the hypothesis that aspects of head injury render selectively vulnerable populations of neurons hyperexcitable and that overexcitation mediated by excitatory amino acid receptors precipitates delayed neuronal degeneration. This study will directly examine the role of excitotoxicity in the degeneration of 3 vulnerable neuronal populations distant to sites of direct cortical injury, 1) specific thalamic relay nuclei which undergo retrograde degeneration following cortical injury, 2) hippocampal pyramidal neurons in the CA1 region of Ammon's horn which undergo delayed degeneration following ischemia due to elevated ICP, and 3) the GABAergic thalamic interneurons of the thalamic reticular nucleus (RT), which are even more sensitive to ischemia due to elevated ICP than the CA1 neurons. The use of the "isolated" ICP or mechanical injury models will allow a more controlled examination of the pathological processes initiated by these two components of concussive brain injury. Findings from these studies will facilitate the identification of compounds which might prevent neurodegeneration in the "combined" injury model which more closely resembles human concussive brain injury. The first specific aim is to determine concussive brain injury. This will be accomplished by characterizing the timecourse of alterations in ICP and depolarization consequent upon cortical impact in a model of concussive injury and comparing the patterns of neuronal loss using classical histological and immunohistochemical techniques seen in this model with those seen in models of cortical ablation or cisternal infusion to elevate ICP. The second specific aim is to investigate the role of excitotoxicity in the death of neurons in populations vulnerable to increased ICP or cortical lesions. This will be accomplished by performing intracranial microdialysis to establish whether the release of endogenous excitatory amino acids (EAAs) brings about excitotoxic conditions, and extracellular unit recording and microiontophoresis of EAA antagonists to determine which class(es) of EAA receptors mediate overexcitation following injury. The third aim is to determine whether prevention of excitotoxicity protects vulnerable neurons from degeneration following either elevated ICP, cortical lesions, or a combination of these insults such as occurs in the cortical impact model of concussive brain injury. Compounds found to prevent overexcitation of vulnerable neuronal populations will be administered to animals prior to or after the different types of injury and their efficacy in preventing neuronal loss will be examined using histological and immunohistochemical techniques 1 week to 3 months later. Because neuronal death in vulnerable populations is delayed from up to several days, antiexcitotoxic drugs can be effectively administered after the insult, offering a unique window for therapeutic intervention in pathological processes which would otherwise lead to the development of persisting neurological deficits. If memory deficits result from CA1 neuronal degeneration and attentional deficits occur as a consequence of RT degeneration following head injury then agents identified as being protective in our animal experiments would be potential candidates for clinical trials of head injury treatment.