Traumatic brain injury (TBI) is an enormous public heath problem; however, targeted therapies are lacking. After severe TBI, ischemia and energy failure frequently occur. Adenosine is a purine nucleotide that acts as a powerful endogenous neuroprotectant during ischemia-induced energy failure by decreasing neuronal metabolism and increasing cerebral blood flow (CBF), among other mechanisms. These effects are mediated through interaction of adenosine with specific receptors. The synergistic effects of increasing CBF and decreasing metabolism suggest an important neuroprotectant role for adenosine after TBI, particularly during secondary insults. Further augmenting the effects of adenosine in brain may reduce neuronal damage. Two strategies to achieve this are particularly relevant to TBI and this application, namely, 1) the inhibition of adenosine metabolism or 2) the local administration of adenosine analogs. Defining four Specific Aims, we will use an established rat model of TBI and applying cerebral microdialysis, contemporary MRI tools, functional outcome testing, and histology, we will first determine the magnitude of the adenosine response (brain interstital levels of adenosine and purine degradation products) to experimental TBI. We will then examine effects of these two defined strategies of augmenting adenosine effects both on key mechanisms of secondary damage (excitotoxicity [brain interstitial levels of glutamate, CBF by perfusion MRI, and Ca++ accumulation in brain by Mn++-contrast-enhanced MRI) and both functional and histopathological outcome. Finally, in a fifth Specific Aim, we will bridge bench to bedside by using cerebral microdialysis methods to define the participation of adenosine (and its relationship to CBF and excitotoxicity) after severe TBI in humans, during the application of contemporary therapeutic interventions (CSF drainage, mannitol, hyperventilation, and barbiturates) in the treatment of intracranial hypertension. If successful, these studies will set the stage for a clinical trial, and provide important mechanistic information on the role of adenosine after TBI in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038087-02
Application #
6188214
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Michel, Mary E
Project Start
1999-08-02
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$256,226
Indirect Cost
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jackson, Edwin K; Kotermanski, Shawn E; Menshikova, Elizabeth V et al. (2017) Adenosine production by brain cells. J Neurochem 141:676-693
Tamburro, Robert F; Jenkins, Tammara L; Kochanek, Patrick M (2016) Strategic Planning for Research in Pediatric Critical Care. Pediatr Crit Care Med 17:e539-e542
Bell, Michael J; Kochanek, Patrick M (2013) Pediatric traumatic brain injury in 2012: the year with new guidelines and common data elements. Crit Care Clin 29:223-38
Adelson, P David; Fellows-Mayle, Wendy; Kochanek, Patrick M et al. (2013) Morris water maze function and histologic characterization of two age-at-injury experimental models of controlled cortical impact in the immature rat. Childs Nerv Syst 29:43-53
Verrier, Jonathan D; Jackson, Travis C; Bansal, Rashmi et al. (2012) The brain in vivo expresses the 2',3'-cAMP-adenosine pathway. J Neurochem 122:115-25
Manole, Mioara D; Kochanek, Patrick M; Foley, Lesley M et al. (2012) Polynitroxyl albumin and albumin therapy after pediatric asphyxial cardiac arrest: effects on cerebral blood flow and neurologic outcome. J Cereb Blood Flow Metab 32:560-9
Drabek, Tomas; Janata, Andreas; Jackson, Edwin K et al. (2012) Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats. Resuscitation 83:517-26
Verrier, Jonathan D; Exo, Jennifer L; Jackson, Travis C et al. (2011) Expression of the 2',3'-cAMP-adenosine pathway in astrocytes and microglia. J Neurochem 118:979-87
Hostler, David; Zhou, Jiangquan; Tortorici, Michael A et al. (2010) Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos 38:781-8
Haselkorn, M Lee; Shellington, David K; Jackson, Edwin K et al. (2010) Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice. J Neurotrauma 27:901-10

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