Previous experiments indicate that following experimental concussive brain injury oxygen free radicals produced during cyclooxygenase metabolism of arachidonic 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. Hypothesis 1: Following concussive brain injury receptor-mediated mechanisms contribute to an increased 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.

Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Kleindienst, Andrea; Dunbar, Jana G; Glisson, Renee et al. (2013) The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury. Acta Neurochir (Wien) 155:151-64
Fazzina, Giovanna; Amorini, Angela M; Marmarou, Christina R et al. (2010) The protein kinase C activator phorbol myristate acetate decreases brain edema by aquaporin 4 downregulation after middle cerebral artery occlusion in the rat. J Neurotrauma 27:453-61
Hartings, Jed A; Strong, Anthony J; Fabricius, Martin et al. (2009) Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma 26:1857-66
Mazzeo, Anna Teresa; Brophy, Gretchen M; Gilman, Charlotte B et al. (2009) Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. J Neurotrauma 26:2195-206
Samuelson, Rod; Mazzeo, Anna; Kunene, Nikki et al. (2006) Synthes Award For Resident Research On Craniofacial And Brain Injury: effect of cyclosporin A, topiramate, or 100% oxygen as proposed ""neuroprotective"" therapies on the neurochemical analytes in patients with severe traumatic brain injury. Clin Neurosurg 53:307-12
Stiefel, Michael F; Tomita, Yoshiyuki; Marmarou, Anthony (2005) Secondary ischemia impairing the restoration of ion homeostasis following traumatic brain injury. J Neurosurg 103:707-14
Stiefel, Michael F; Marmarou, Anthony (2002) Cation dysfunction associated with cerebral ischemia followed by reperfusion: a comparison of microdialysis and ion-selective electrode methods. J Neurosurg 97:97-103
Yamamoto, M; Marmarou, C R; Stiefel, M F et al. (1999) Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension. J Neurotrauma 16:487-500
Barzo, P; Marmarou, A; Fatouros, P et al. (1997) MRI diffusion-weighted spectroscopy of reversible and irreversible ischemic injury following closed head injury. Acta Neurochir Suppl 70:115-8
Marmarou, A; Barzo, P; Fatouros, P et al. (1997) Traumatic brain swelling in head injured patients: brain edema or vascular engorgement? Acta Neurochir Suppl 70:68-70

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