The goal of the proposed experiments remains the characterization of cellular mechanisms underlying glutamate neurotoxicity, a process which likely participates in the neuronal degeneration associated with certain acute or chronic neurological diseases. Furthermore, independent of direct disease implications, elucidation of these mechanisms may yield insights into the general nature of neuronal injury, and thus aid in the development of neuroprotective strategies. To resolve specific cellular and molecular events, experiments will be carried out in vitro, either in primary cortical cell cultures, or in mammalian cell lines transfected with cloned glutamate receptors. Answers to three questions will be sought: l. How does metabotropic glutamate receptor activation influence excitotoxicity? 2. Does the calcium influx triggered by activation of different defined glutamate receptors predict subsequent excitotoxic death even in non-neuronal, HEK 293 cells? 3. Which pathways mediate the late toxic influx of Ca2+ into neurons that follows brief intense NMDA receptor activation? In particular, does the NMDA-induced late inward current described by Chen and Wong on hippocampal neurons, play a role? Improved definition of the cellular mechanisms underlying glutamate neurotoxicity could lead to the development of new therapeutic maneuvers designed to attenuate the neuronal destruction associated with several disease states. Furthermore, such a definition would likely provide sorted insight into the general problem of neuronal cell injury. and might thus have valuable implications for understanding human neurological illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030337-09
Application #
2891828
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Murphy, Diane
Project Start
1991-09-30
Project End
2001-03-31
Budget Start
1999-08-01
Budget End
2001-03-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sheline, Christian T; Zhu, Julia; Zhang, Wendy et al. (2013) Mitochondrial inhibitor models of Huntington's disease and Parkinson's disease induce zinc accumulation and are attenuated by inhibition of zinc neurotoxicity in vitro or in vivo. Neurodegener Dis 11:49-58
Carter, Russell E; Aiba, Isamu; Dietz, Robert M et al. (2011) Spreading depression and related events are significant sources of neuronal Zn2+ release and accumulation. J Cereb Blood Flow Metab 31:1073-84
Sheline, Christian T; Cai, Ai-Li; Zhu, Julia et al. (2010) Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+. Eur J Neurosci 32:894-904
Suh, Sang Won; Won, Seok Joon; Hamby, Aaron M et al. (2009) Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats. J Cereb Blood Flow Metab 29:1579-88
Cai, Ai-Li; Zipfel, Gregory J; Sheline, Christian T (2006) Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway. Eur J Neurosci 24:2169-76
Sheline, C T; Wei, L (2006) Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo. Neuroscience 140:235-46
Sheline, Christian T; Choi, Dennis W (2004) Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. Ann Neurol 55:645-53
Sheline, Christian T; Takata, Toshihiro; Ying, Howard et al. (2004) Potassium attenuates zinc-induced death of cultured cortical astrocytes. Glia 46:18-27
Snider, B J; Moss, J L; Revilla, F J et al. (2003) Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults. Neuroscience 120:617-25
Sheline, Christian T; Wang, Hongmin; Cai, Ai-Li et al. (2003) Involvement of poly ADP ribosyl polymerase-1 in acute but not chronic zinc toxicity. Eur J Neurosci 18:1402-9

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