IONIC FLUXES AND NEURONAL DYSFUNCTION IN BRAIN INJURY

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A major goal of therapies for traumatic brain injury is to provide an ideal milieu for recovery of neuronal cells which are metabolically deranged but not mechanically and irreversibly damaged. The purpose of this proposal is to delineate the mechanisms of such metabolic derangements of neuronal cells subjected to sublethal traumatic injury. Our preliminary studies revealed that massive ionic fluxes are a major event taking place in these cells. Our preliminary studies also suggest that indiscriminate release of neurotransmitter, especially excitatory amino acids, and transmitter- dependent ion channels play a vital role in producing these ionic events. Changes in ionic permeability in response to neurotransmitter release are characteristic of the neuron as an excitable cell. Thus, these phenomena are unique to neuronal cells as compared with any other cell in the body. There are a number of reasons to expect that even transient ionic perturbation triggers long-lasting metabolic derangements including lactate accumulation. Our previous observation indicated that lactate definitely increases in CSF as well as brain tissue during the initial 60 min. following traumatic brain injury. Since detrimental effects of lactate accumulation in ischemic brain injury have repeatedly been demonstrated, lactate accumulation is likely to be related to the mechanisms that render the traumatized neuronal cells more vulnerable to a second insult. Thus, the immediate goals of this proposal are to determine: (1) the existence and extent of ionic fluxes following mold to moderate traumatic brain injury: (2) the mechanism of the massive ionic fluxes: and (3) their importance in the process of lactate accumulation. We will extensively utilize brain microdialysis technique to answer the question posed in this proposal. This technique enables us to monitor ionic environment and other neurochemical changes in the extracellular space (ECS) simultaneously and provides a means for administering various drugs into the ECS. If the hypotheses are proven to be true, a major advance will have been made in understanding the sequence of metabolic derangements unique to traumatic brain insult which begins from the moment of injury. The long-term goals of our research based on the data from the experiments proposed here are: (1) to determine the mechanisms of lactate accumulation following traumatic brain injury; and (2) to identify the ideal ECS milieu for protection of the traumatized neuronal cells from lactate accumulation. Ultimately this information would lead to improved treatment of traumatic brain injury.