ROLE OF MAGNESIUM IN THE PATHOPHYSIOLOGY OF BRAIN INJURY

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Head injuries pose a significant and unique health problem in the United States. Of people that survive head trauma, over 60,000 each year experience residual neurological dysfunction These neurological deficits appear to be caused by direct mechanical disruption of neuronal pathways and through secondary or delayed mechanisms that develop over a period of hours to days following the traumatic insult. Although part of the delayed damage to the central nervous system (CNS) after traumatic injury appears to result from the release or activation of endogenous autodestructive factors, the fundamental mechanisms underlying secondary injury are poorly understood and current therapies largely unsatisfactory. Recent work from our laboratory suggests that decline in brain magnesium (Mg++) may be a critical factor in the pathophysiological sequelae of traumatic brain injury. Because Mg++ is mandatory for all ATP producing and consuming reactions, it regulates cellular bioenergetic state and exerts considerable control over a large diversity of metabolic and ionic flux pathways. Changes in tissue Mg++ may therefore be a common mechanism linking apparently unrelated CNS injury factors and the response to specific treatments. The proposed studies will examine the pathophysiological role of Mg++ in secondary brain injury using a model of fluid-percussion traumatic brain injury in the rat. Changes in total, extracellular and intracellular free brain Mg++ concentrations after brain injury will be characterized and related to time course and injury severity. Magnesium changes will also be correlated with alterations in cellular bioenergetic state (31P NMR), mitochondrial function, as well as changes in other brain cation concentrations (Ca++, Na+, K+, Zn++) and tissue water content. The effect of Mg deficiency (dietary restriction) and Mg supplementation on neurochemical, histopathological and neurobehavioral outcome after brain injury will be examined. To evaluate the role of the magnesium-gated excitatory amino acid (EAA) ion channel in brain injury, changes in extracellular and tissue EAA changes to be measured after brain injury and noncompetitive EAA receptor antagonists MK-801 and CGS-19755 will be evaluated, with and without Mg++ supplementation, for their efficacy in the treatment of brain injury. These studies will expand our understanding of the fundamental pathophysiological mechanisms that contribute to irreversible tissue damage after traumatic brain injury, and may lead to the development of effective new therapeutic approaches for the treatment of brain injury.