For seven years we have investigated physical trauma on the cellular level in culture to determine quantitatively the fundamental reactions and subsequent repair responses of CNS neurons to potentially reversible injuries. Several interventions were identified that showed promise for slowing or arresting the sequence of intracellular deterioration following physical (ion deregulation) injury. It is our objective to explore systematically the mechanisms and limits of these interventions and to develop an optimum acute phase protocol for combined application that will achieve substantial cell survival after physical injury without impairing normal neuronal functions. Our three general goals are to: (1) arrest damage spread; (2) support and enhance intracellular repair; and (3) return the neurons to normal conditions without secondary damage. All three goals can be investigated effectively in cell culture by observing cell survival, morphological changes and ultrastructural changes in lesioned neurons exposed to individual and combined interventions, and by comparing changes in the activity of networks of uninjured neurons before and after exposure to individual or combined treatments.
As specific aims, we propose (1) to test a modified ionic environment (low Ca++, low Na+, low Cl-, +/- high K+); (2) to explore in detail the mechanisms of hypothermic protection and hypothermic stress; (3) to enhance lesion resealing with large liposomes (supramolecular bandages); (4) to enhance cellular repair processes by liposome delivery of ATP and/or Mg++; (5) to screen in vitro promising acute phase treatments such as sodium thiopental and methylprednisolone, and (6) to establish an acute phase intervention protocol that uses an optimum combination of specific interventions. When necessary to avoid secondary damage (i.e. calcium paradox), different return routes to normal conditions will be explored (hypothermia, slow temporal ramping of ionic concentrations, etc.). It is our conviction that detailed investigations of cellular and network reactions in culture can be used for rapid and cost-effective screening of potential CNS injury treatments. These investigations should provide a valuable data base for guiding future whole animal experiments and should help to accelerate the development of effective acute phase interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS029683-01
Application #
3416551
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-09-01
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of North Texas
Department
Type
Schools of Arts and Sciences
DUNS #
City
Denton
State
TX
Country
United States
Zip Code
76203