Recent work from our laboratory has suggested that changes in the magnesium ion (Mg2+) may play an important role in mediating the pathophysiological sequelae of traumatic brain injury (TBI). Magnesium is a critical ion in the brain for the regulation of cellular bioenergetics and changes in brain Mg2+ concentrations after trauma can potentially alter regional brain metabolism, cerebrovascular function and intracellular calcium flux, thereby directly affecting post-traumatic neuronal susceptibility to damage. The objects of the studies outlined in this application are to (1) characterize changes in extracellular and intracellular concentrations of Mg2+ after experimental brain injury, (2) determine whether Mg2+ deficiency alters post-traumatic outcome and whether maintenance of Mg2+ homeostasis is neuroprotective after brain injury, (3) examine the efficacy of pharmacotherapies that interact with the Mg2+ homeostasis is neuroprotective after brain injury, complex, and (4) determine whether the beneficial effects of diverse pharmacotherapies known to be effective in brain injury are associated with the recovery of tissue Mg2+ and enhanced bioenergetics status. Extracellular concentrations of Mg2+ will be characterized over time after fluid- percussion (FP) brain injury of graded severity int he rat using intracerebral microdialysis and atomic absorption spectrophotometry. Changes in intracellular Mg2+ will be assessed using phosphorus (P) nuclear magnetic resonance (NMR) spectroscopy. Post-injury changes in extracellular and intracellular Mg2+ will be related to alterations in regional cerebral blood flow (rCBF, radiolabeled microspheres/iodoantipyrine autoradiography), cerebral bioenergetics (P NMR), histopathological damage, neurologic (motor), and cognitive (Morris Water Maze) deficits. Molecular biology techniques will be employed to examine the relationship between post-traumatic alterations in brain magnesium and expression of mRNA for heat-shock protein (HSP-72) and the immediate early genes (IEG) c-fos/c-jun. In order to begin to determine the fate of the magnesium ion following trauma, we will measure magnesium concentrations in plasma and cerebrospinal fluid (CSF). We will also evaluate whether Mg2+ deficiency following dietary restriction will affect post-traumatic outcome and whether post-injury treatment with Mg2+ will improve post-traumatic cerebrovascular, metabolic, histopathologic, and behavioral function. Finally, the therapeutic efficacy of the competitive NMDA antagonist CGS19755, the AMPA/KA receptor antagonist GYKk152466, the novel presynaptic glutamate release blocker BW619C89, and the NMDA-associated glycine receptor antagonist kynurenate will be evaluated for their effects on post-traumatic rCBF, metabolism, neuronal damage, and behavioral function. A """"""""critical window"""""""" for post-traumatic pharmacologic intervention will be assessed using the most optimal combination of pharmacotherapies. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie cerebrovascular, metabolic, histologic, and behavioral damage associated with TBI and result in the development of new and more effective therapeutic approaches to the treatment of brain trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026818-05
Application #
2266128
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-12-01
Project End
1999-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tomasevic, Gregor; Raghupathi, Ramesh; Scherbel, Uwe et al. (2010) Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice. J Neurosci Res 88:3414-23
Raghupathi, Ramesh; Strauss, Kenneth I; Zhang, Chen et al. (2003) Temporal alterations in cellular Bax:Bcl-2 ratio following traumatic brain injury in the rat. J Neurotrauma 20:421-35
Raghupathi, Ramesh; Muir, Judith K; Fulp, Carl T et al. (2003) Acute activation of mitogen-activated protein kinases following traumatic brain injury in the rat: implications for posttraumatic cell death. Exp Neurol 183:438-48
Williams, S; Raghupathi, R; MacKinnon, M A et al. (2001) In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol (Berl) 102:581-90
Shaw, K; MacKinnon, M A; Raghupathi, R et al. (2001) TUNEL-positive staining in white and grey matter after fatal head injury in man. Clin Neuropathol 20:106-12
LaPlaca, M C; Zhang, J; Raghupathi, R et al. (2001) Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 18:369-76
Saatman, K E; Bareyre, F M; Grady, M S et al. (2001) Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency. J Neuropathol Exp Neurol 60:183-94
Laurer, H L; McIntosh, T K (2001) Pharmacologic therapy in traumatic brain injury: update on experimental treatment strategies. Curr Pharm Des 7:1505-16
Blaha, G R; Raghupathi, R; Saatman, K E et al. (2000) Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits. Neuroscience 99:483-93
Morrison 3rd, B; Eberwine, J H; Meaney, D F et al. (2000) Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization. Neuroscience 96:131-9

Showing the most recent 10 out of 60 publications