A fundamental problem in the neuroprotection field that remains unsolved is whether or not traumatically injured brain cells can be rescued from death. Essential concepts such as survival time and functionality of injured cells, and the "point of no return" from eventual demise have not been adequately explored in traumatic brain injury (TBI) models. Loss of plasmalemma integrity is a common feature of cellular injury and death in experimental TBI. Using propidium iodide (PI) to label cells with loss of plasmalemma integrity in vivo, we developed a PI pulse labeling protocol to follow the fate of injured brain cells after controlled cortical impact (CCI) in mice. Our findings suggest that although loss of plasmalemma integrity is a biomarker of fatal injury in many cells, a subset of PI+ cells may be rescuable by appropriate therapeutic agents. Based on these data, we propose three Specific Aims to test the central hypothesis that loss of plasmalemma integrity is a therapeutic target to rescue injured cells after TBI:
Aim 1 : Test the hypothesis that loss of plasmalemma integrity early versus late following controlled cortical impact is a biomarker of fatal versus rescuable injury, respectively.
Aim 2 : Test the hypothesis that loss of plasmalemma integrity is an active process mediated by TNF alpha and Fas receptors beginning early (minutes) after TBI, using in vitro and in vivo trauma models and mice or primary cortical neurons deficient in TNF/Fas.
Aim 3 : Test the hypothesis that restoration of plasmalemma integrity is a therapeutic target to rescue traumatically injured brain cells after CCI. Use poloxamer P188, a non-ionic amphiphilic triblock copolymer membrane resealing agent, and necrostatin-1, a specific inhibitor of TNF/Fas induced cell death, to reduce plasmalemma damage and acute cell death and improve functional outcome after CCI in mice. The proposed studies are intended to show that loss of plasmalemma integrity is a therapeutic target to rescue injured cells in patients with TBI. Work in this proposed project could impact public health by developing a new treatment for traumatic brain injury, and by developing tools that could assist researchers to better assess the potential value of therapeutic agents for brain and spinal cord injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061255-05
Application #
8197790
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2008-01-15
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$366,238
Indirect Cost
$151,863
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Zhu, Xiaoxia; Tao, Luyang; Tejima-Mandeville, Emiri et al. (2012) Plasmalemma permeability and necrotic cell death phenotypes after intracerebral hemorrhage in mice. Stroke 43:524-31
Mbye, Lamin H; Keles, Eyup; Tao, Luyang et al. (2012) Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 32:515-24
You, Zerong; Savitz, Sean I; Yang, Jinsheng et al. (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 28:1564-73