This competitive renewal seeks continued support for a program project which, over its history, has made a dedicated effort to better understand the complex pathobiology of human traumatic brain injury (TBI) and, based upon such understanding, develop more rational therapeutic strategies. The theme of this application centers on the role of receptor-mediated neuronal injury and its relation to the release of excessive excitatory neurotransmitters. In the laboratory, this application moves on the premise that an initial, excessive release of excitatory neurotransmitters, elicited by the TBI, causes receptor-mediated injury, leading to neuronal dysfunction and/or death. In this vane, one laboratory effort assesses the damaging consequences of increased neurotransmitter release in TBI to determine if transmitter-related neurotoxicity can be amplified by synergetic mechanisms. Another laboratory project examines the consequences of this excessive transmitter release in terms of excessive receptor activation to elicit the altered coupling of the neurotransmitter receptors to their effector molecules. Another laboratory component examines the role of these abnormal receptor-mediated interactions by examining their long-term consequences in terms of cognitive dysfunction. Lastly, in the lab, the concept of receptor-mediated change will be considered not only in the context of generalized neuroexcitation but also in the context of diffuse injury, complicated by focal insult/deafferentation. In the clinical setting, efforts will be made to better document the role of excitatory neurotransmitters in the pathobiology of TBI. Intracerebral microdialysis will be employed in patients to measure local excitatory amino acid levels as well as ionic flux and lactate/pyruvate ratios in varied brain regions. These microdialysis studies will be conducted in concert with studies of CBF and ICP changes. These CBF changes will be provided as an extension of another project which will examine the genesis of the altered early ischemia seen after TBI. Lastly, in this same patient population, studies will be performed to better elucidate the mechanisms responsible for the brain swelling and subsequent ICP rise seen after brain injury. Efforts will be made to determine if brain edema is derived primarily from cellular swelling due to either ischemic or neurotoxic processes. Collectively, we believe that all of the above projects are logical outgrowths of our previous research efforts. They explore important issues directly relevant to the pathobiology of human TBI and most likely will suggest new therapeutic approaches for the more rational treatment of human TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS012587-19
Application #
2262450
Study Section
Special Emphasis Panel (SRC (06))
Project Start
1979-04-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
19
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Neurosurgery
Type
Schools of Medicine
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

Showing the most recent 10 out of 14 publications