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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026818-02
Application #
3412873
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Raghupathi, Ramesh; Muir, Judith K; Fulp, Carl T et al. (2003) Acute activation of mitogen-activated protein kinases following traumatic brain injury in the rat: implications for posttraumatic cell death. Exp Neurol 183:438-48
Raghupathi, Ramesh; Strauss, Kenneth I; Zhang, Chen et al. (2003) Temporal alterations in cellular Bax:Bcl-2 ratio following traumatic brain injury in the rat. J Neurotrauma 20:421-35
Williams, S; Raghupathi, R; MacKinnon, M A et al. (2001) In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol (Berl) 102:581-90
Shaw, K; MacKinnon, M A; Raghupathi, R et al. (2001) TUNEL-positive staining in white and grey matter after fatal head injury in man. Clin Neuropathol 20:106-12
LaPlaca, M C; Zhang, J; Raghupathi, R et al. (2001) Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 18:369-76
Saatman, K E; Bareyre, F M; Grady, M S et al. (2001) Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency. J Neuropathol Exp Neurol 60:183-94
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Blaha, G R; Raghupathi, R; Saatman, K E et al. (2000) Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits. Neuroscience 99:483-93
Morrison 3rd, B; Eberwine, J H; Meaney, D F et al. (2000) Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization. Neuroscience 96:131-9

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