Abstract

The goal of the proposed experiments is a continued characterization of the cellular mechanisms underlying glutamate neurotoxicity, a process which may participate in the neuronal degeneration associated with certain acute or chronic neurological diseases, including Alzheimer's disease. Even is glutamate neurotoxicity is not involved in the pathogenesis of any chronic neurodegenerative diseases, it is proposed that elucidation of its underlying mechanisms could yield valuable insights into some common principles of neuronal cell injury. To achieve cellular and molecular resolution, investigations will take place in an established dissociated murine cortical cell culture model system. Using pharmacological, physiological, and neurochemical approaches, including neurotoxicity assays, histochemical stains, whole cell recording, HPLC, 45Ca2+ accumulation, and fura-2 videomicroscopy, answers to these four questions will be specifically sought: 1) What is the role of the """"""""metabotropic"""""""" glutamate receptor in glutamate neurotoxicity? 2) What is the role of calcium in glutamate neurotoxicity? 3) What is the role of lipid peroxidation in mediating glutamate neurotoxicity? and 4) Why are cortical neurons containing high concentrations of NADPH-diaphorase resistant to NMDA receptor- mediated injury? The proposed experiments will provide new information regarding the nature of glutamate neurotoxicity and could lead to the development of therapeutic approaches designed to reduce pathological neuronal cell death in Alzheimer's disease or related disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030337-02
Application #
3417256
Study Section
Special Emphasis Panel (SRC (34))
Project Start
1991-09-30
Project End
1995-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

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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