Previous experiments indicate that following experimental concussive brian injury oxygen free radicals produced during cyclooxygenase metabolism of arachidonic acid cause endothelial lesions, dilation, reduce responsiveness to hypocapnia and abnormal responsiveness to acetylcholine in acid cause endothelial lesions, dilation, reduced responsiveness to hypocapnia and abnormal responsiveness to acetylcholine in cerebral arterioles. We now have evidence that specific agonists, including acetylcholine and bradykinin, may be in part responsible for stimulating arachidonic acid metabolism following injury. We therefore wish to test the following hypotheses (see figure). Hypothesis 1: Following concussive brain injury receptor-mediated mechanisms contribute to an increase metabolism of polyunsaturated fatty acids and the production of oxygen radicals which cause cerebrovascular and brain dysfunction. Hypothesis 2: Pharmacologic inhibition of fatty acid metabolism, free radical production or free radical action will reduce the cerebrovascular dysfunction caused by traumatic brain injury (TBI). Our general aims are to understand 1) factors responsible for initiation and regulation of fatty acid metabolism following injury, 2) the pathways and products of this metabolism, 3) the cerebrovascular consequences of increased fatty acid metabolism and radical production and 4) how pharmacologic intervention can prevent, reduce or reverse the injury process. To accomplish our aims we will utilize microscopy and radioimmunoassay to correlate simultaneous in vivo arteriolar diameter responses and in vivo cyclooxygenase and lipoxygenase synthetic responses. We will also employ gas chromatography/mass spectrometry to identify and measure fatty acids and their metabolites. Little is known about regulation of the changes in fatty acid metabolism and the concomitant cerebrovascular consequences of increased oxygen radical production following brain injury. The proposed studies will address these problems and are consistent with our long term goal of elucidating chemical mediators of, and therapeutic agents for, brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027214-11
Application #
6187221
Study Section
Neurology A Study Section (NEUA)
Program Officer
Michel, Mary E
Project Start
1989-04-01
Project End
2002-05-14
Budget Start
2000-04-01
Budget End
2002-05-14
Support Year
11
Fiscal Year
2000
Total Cost
$278,300
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Ellis, Earl F; Willoughby, Karen A; Sparks, Sallie A et al. (2007) S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases trauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons. J Neurochem 101:1463-70
Willoughby, Karen A; Kleindienst, Andrea; Muller, Christian et al. (2004) S100B protein is released by in vitro trauma and reduces delayed neuronal injury. J Neurochem 91:1284-91
Floyd, Candace L; Rzigalinski, Beverly A; Sitterding, Heather A et al. (2004) Antagonism of group I metabotropic glutamate receptors and PLC attenuates increases in inositol trisphosphate and reduces reactive gliosis in strain-injured astrocytes. J Neurotrauma 21:205-16
Chen, Tao; Willoughby, Karen A; Ellis, Earl F (2004) Group I metabotropic receptor antagonism blocks depletion of calcium stores and reduces potentiated capacitative calcium entry in strain-injured neurons and astrocytes. J Neurotrauma 21:271-81
Goforth, Paulette B; Ellis, Earl F; Satin, Leslie S (2004) Mechanical injury modulates AMPA receptor kinetics via an NMDA receptor-dependent pathway. J Neurotrauma 21:719-32
Neary, Joseph T; Kang, Yuan; Willoughby, Karen A et al. (2003) Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J Neurosci 23:2348-56
Weber, John T; Rzigalinski, Beverly A; Ellis, Earl F (2002) Calcium responses to caffeine and muscarinic receptor agonists are altered in traumatically injured neurons. J Neurotrauma 19:1433-43
Ahmed, Syed M; Weber, John T; Liang, Shi et al. (2002) NMDA receptor activation contributes to a portion of the decreased mitochondrial membrane potential and elevated intracellular free calcium in strain-injured neurons. J Neurotrauma 19:1619-29
Floyd, C L; Rzigalinski, B A; Weber, J T et al. (2001) Traumatic injury of cultured astrocytes alters inositol (1,4,5)-trisphosphate-mediated signaling. Glia 33:12-23
Weber, J T; Rzigalinski, B A; Ellis, E F (2001) Traumatic injury of cortical neurons causes changes in intracellular calcium stores and capacitative calcium influx. J Biol Chem 276:1800-7

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