The long-term objective of this research is to examine mechanisms of acute astrocyte damage and death following traumatic brain injury and to develop treatment strategies for attenuating these injury mechanisms. We address anatomical and functional consequences of traumatic brain injury using neuroanatomical, neuroimaging, and behavioral techniques with the goal of understanding the pathological mechanism and developing therapeutic strategies. Traumatic brain injury is a significant health problem that results in more than 230,000 hospitalizations and 50,000 deaths per year in the USA. Survivors of TBI are often left with long-term disability. Astrocytes are the most numerous type of gila cells and provide many important functions to support neurons including exchange of metabolic and nutritional material, clearance of neurotransmitters, and maintenance of ion concentrations in the vicinity of neurons. Astrocyte function is likely to have great importance after traumatic brain injury when extracellular glutamate and potassium concentrations are elevated. Severe damage to astrocytes occurs within hours after traumatic brain injury in brain regions that later exhibit significant neuronal cell degeneration and loss. We hypothesize that the early damage to astrocytes is due, in part, to large increases in intracellular sodium that enter astrocytes through sodium-dependent glutamate transporters and by activation of the type 1 sodium proton exchanger. The resulting increased intracellular sodium promotes reversal of the astrocyte sodium-calcium exchanger creating an excess of intracellular calcium that ultimately leads to astrocyte death. We will test and refine these hypotheses using established cell culture injury models. We will subject cells to traumatic injury and manipulate various sodium and calcium transporters while measuring intracellular ion concentrations and cell viability. This information will be used to explore novel pharmacological manipulations targeted at these sodium and calcium injury mechanisms. In these in vivo therapeutic studies we will measure astrocyte and neuronal viability using anatomical markers, measure brain edema using magnetic resonance imaging, and measure functional outcome using behavioral measures of sensorimotor function and learning and memory following traumatic brain injury in the rat.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045136-04
Application #
6984080
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Hicks, Ramona R
Project Start
2002-12-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2009-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$344,400
Indirect Cost
Name
University of California Davis
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Shahlaie, Kiarash; Gurkoff, Gene G; Lyeth, Bruce G et al. (2013) Neuroprotective effects of SNX-185 in an in vitro model of TBI with a second insult. Restor Neurol Neurosci 31:141-53
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Harley, William; Floyd, Candace; Dunn, Tamara et al. (2010) Dual inhibition of sodium-mediated proton and calcium efflux triggers non-apoptotic cell death in malignant gliomas. Brain Res 1363:159-69
Shahlaie, Kiarash; Lyeth, Bruce G; Gurkoff, Gene G et al. (2010) Neuroprotective effects of selective N-type VGCC blockade on stretch-injury-induced calcium dynamics in cortical neurons. J Neurotrauma 27:175-87
Di Giorgio, Anthony M; Hou, Yongjin; Zhao, Xueren et al. (2008) Dimethyl sulfoxide provides neuroprotection in a traumatic brain injury model. Restor Neurol Neurosci 26:501-7
Zhang, Bin; West, Eric J; Van, Ken C et al. (2008) HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res 1226:181-91
Cox, Christopher D; West, Eric J; Liu, Ming Cheng et al. (2008) Dicyclomine, an M1 muscarinic antagonist, reduces biomarker levels, but not neuronal degeneration, in fluid percussion brain injury. J Neurotrauma 25:1355-65
Zhao, Xueren; Gorin, Fredric A; Berman, Robert F et al. (2008) Differential hippocampal protection when blocking intracellular sodium and calcium entry during traumatic brain injury in rats. J Neurotrauma 25:1195-205
Floyd, Candace L; Lyeth, Bruce G (2007) Astroglia: important mediators of traumatic brain injury. Prog Brain Res 161:61-79
Zhong, Chunlong; Zhao, Xueren; Van, Ken C et al. (2006) NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. J Neurochem 97:1015-25

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