Supplemental Application 1RO1 NS048589: """"""""13C and 15N MRS study of glutamate control in epilepsy"""""""". This supplemental application is submitted to complete the upgrade of our 4.7 Tesla MR spectrometer to Bruker Avance console. Substantial progress has been made in Specific Aim #1 of our awarded Grant, viz study of the kinetics of glutamine (GLN) transport from the glia to the extracellular fluid (ECF) and the mechanism of neuronal uptake of GLNECF, which had been a missing link in the glutamine/glutamate cycle. For further progress, upgrade of our 20-year-old animal scanner is urgently needed.
Our Specific Aim #2 proposes to examine how glutamate (GLU) excitotoxicity may cause epileptic seizures. This will be studied using the chronic kainate-induced (KA) epileptic rat model, which most closely resembles human temporal lobe epilepsy (TIE). Excessive release of the neurotransmitter glutamate (GLU) into ECF and/or impaired uptake of GLUECF into astrocytes can lead to excessive stimulation of the GLU receptors and to neuronal degeneration (GLU excitotoxicity). In vivo flux rates of GLU release and uptake will be measured in the lesioned and contralateral hippocampus, and correlated with (a) electrophysiological and behavioral seizures, and (b) morphological changes which had, until recently, been detected histologically in post- mortem brain. Recent advances in MRI/MRS raise an exciting possibility that histopathological or metabolic changes such as mossy fiber sprouting (observed in both human TLE and KA rats), neuronal degeneration, reduction in the neuronal marker N-acetylaspartate, and edema due to astrocyte swelling, may be detected non-invasively from 1-2 microliter of rodent brain. Upgrade to Bruker Avance console will provide state-of- the-art imaging and spectroscopy capability which can permit non-invasive longitudinal monitoring of these changes in KA rats. This will allow determination of (a) how the onset and propagation of seizures are correlated with the morphological and metabolic changes in hippocampal sub-regions, and (b) whether the seizures are the result of abnormal GLU release, impaired GLU clearance by glial transporters, or a combination of these processes. Together these studies will contribute to a better understanding of the regulatory events of the GLN/GLU cycle in the KA model and lead to more effective preventions of excitotoxicity in human epilepsy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS048589-02S1
Application #
7257997
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jacobs, Margaret
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$75,000
Indirect Cost
Name
Huntington Medical Research Institutes
Department
Type
DUNS #
077978898
City
Pasadena
State
CA
Country
United States
Zip Code
91101
Kanamori, Keiko (2017) Faster flux of neurotransmitter glutamate during seizure - Evidence from 13C-enrichment of extracellular glutamate in kainate rat model. PLoS One 12:e0174845
Kanamori, Keiko (2017) In vivo N-15 MRS study of glutamate metabolism in the rat brain. Anal Biochem 529:179-192
Kanamori, Keiko (2015) Disinhibition reduces extracellular glutamine and elevates extracellular glutamate in rat hippocampus in vivo. Epilepsy Res 114:32-46
Cassidy, M C; Chan, H R; Ross, B D et al. (2013) In vivo magnetic resonance imaging of hyperpolarized silicon particles. Nat Nanotechnol 8:363-8
Ross, Brian D (2013) High-field MRS in clinical drug development. Expert Opin Drug Discov 8:849-63
Kanamori, Keiko; Ross, Brian D (2013) Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus. Epilepsy Res 107:20-36
Zacharias, Niki M; Chan, Henry R; Sailasuta, Napapon et al. (2012) Real-time molecular imaging of tricarboxylic acid cycle metabolism in vivo by hyperpolarized 1-(13)C diethyl succinate. J Am Chem Soc 134:934-43
Kanamori, Keiko; Ross, Brian D (2011) Chronic electrographic seizure reduces glutamine and elevates glutamate in the extracellular fluid of rat brain. Brain Res 1371:180-91
Lingwood, Mark D; Siaw, Ting Ann; Sailasuta, Napapon et al. (2010) Continuous flow Overhauser dynamic nuclear polarization of water in the fringe field of a clinical magnetic resonance imaging system for authentic image contrast. J Magn Reson 205:247-54
Bhattacharya, Pratip; Ross, Brian D; Bünger, Rolf (2009) Cardiovascular applications of hyperpolarized contrast media and metabolic tracers. Exp Biol Med (Maywood) 234:1395-416

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