Recent experimental evidence supports a role for AMPA/KA-type glutamate receptors in mediating ischemic neuronal death, such as occurs in stroke. Free radicals have also been implicated in the injury process that leads to ischemic cell death. The main objective of this proposal is to determine the involvement of free radical formation in AMPA/KA receptor- mediated neuronal death in oxygen-glucose deprivation in vitro and ischemic brain injury in vivo. The central hypothesis to be tested is that generation of oxygen free radicals contributes to AMPA/KA receptor- mediated neuronal death in oxygen-glucose deprivation in vitro and ischemia/reperfusion in vivo.
Three specific aims and related research plans are directed at testing this hypothesis. The involvement of free radicals in AMPA/KA receptor-mediated cell death will be assessed in oxygen-glucose deprivation in vitro using mouse brain cortical cultures, and in two in vivo ischemia models (rat global ischemia and focal ischemia). In most experiments, NMDA receptors will be blocked to 'unmask' the contribution of AMPA/KA receptors. Production of free radicals will be measured using state-of-the-art methods for detecting free radicals, such as Electron Spin Resonance (ESR), and salicylate trapping/HPLC for detection of hydroxyl radical. Trapping agents (spin- traps for ESR or salicylate) will be delivered to the cells by microdialysis (in vivo) or by direct application to cells (in vitro). Protection by anti-oxidants/radical scavengers against the AMPA/KA receptor-mediated component of oxygen-glucose deprivation injury in vitro and ischemic injury in vivo will also be examined. Clarifying the sources of free radicals and the events that trigger their production may assist in the development of improved therapy for CNS ischemia.

Project Start
1999-02-01
Project End
2000-09-29
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Guilliams, Kristin P; Fields, Melanie E; Ragan, Dustin K et al. (2017) Large-Vessel Vasculopathy in Children With Sickle Cell Disease: A Magnetic Resonance Imaging Study of Infarct Topography and Focal Atrophy. Pediatr Neurol 69:49-57
Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi et al. (2016) Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles. Neurosci Res 107:57-62
Becker, April M; Meyers, Eric; Sloan, Andrew et al. (2016) An automated task for the training and assessment of distal forelimb function in a mouse model of ischemic stroke. J Neurosci Methods 258:16-23
Osei-Owusu, Patrick; Knutsen, Russell H; Kozel, Beth A et al. (2014) Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency. Am J Physiol Heart Circ Physiol 306:H654-66
Hyrc, Krzysztof L; Minta, Akwasi; Escamilla, P Rogelio et al. (2013) Synthesis and properties of Asante Calcium Red--a novel family of long excitation wavelength calcium indicators. Cell Calcium 54:320-33
Shen, Hua; Hyrc, Krzysztof L; Goldberg, Mark P (2013) Maintaining energy homeostasis is an essential component of Wld(S)-mediated axon protection. Neurobiol Dis 59:69-79
Murata, Takahiro; Dietrich, Hans H; Xiang, Chuanxi et al. (2013) G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats. Stroke 44:779-85
Kraft, Andrew W; Hu, Xiaoyan; Yoon, Hyejin et al. (2013) Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 27:187-98
Xiao, Qingli; Ford, Andria L; Xu, Jan et al. (2012) Bcl-x pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia. J Neurosci 32:13587-96
Wacker, Bradley K; Perfater, Jennifer L; Gidday, Jeffrey M (2012) Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway. J Neurochem 123:954-62

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