Preconditioning induces tolerance by suppressing glutamate release in neuron culture ischemia models

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DOIResolve DOI: http://doi.org/10.1111/j.1471-4159.2012.07791.x
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TypeArticle
Journal titleJournal of Neurochemistry
ISSN0022-3042
Volume122
Issue2
Pages470481; # of pages: 12
Subjectexcitotoxicity; glutamate; neuroprotection; preconditioning; synaptic scaling; tolerance
AbstractThis study determined how preconditioned neurons responded to oxygen-glucose deprivation (OGD) to result in neuroprotection instead of neurotoxicity. Neurons preconditioned using chronically elevated synaptic activity displayed suppressed elevations in extracellular glutamate ([glutamateex]) and intracellular Ca²+ (Ca²+ in) during OGD. The glutamate uptake inhibitor TBOA induced neurotoxicity, but at a longer OGD duration for preconditioned cultures, suggestive of delayed up-regulation of transporter activity relative to non-preconditioned cultures. This delay was attributed to a critically attenuated release of glutamate, based on tolerance observed against insults mimicking key neurotoxic signaling during OGD (OGD-mimetics). Specifically, in the presence of TBOA, preconditioned neurons displayed potent protection to the OGD-mimetics: ouabain (a Na+/K+ ATPase inhibitor), high 55 mM KCl extracellular buffer (plasma membrane depolarization), veratridine (a Na+ ionophore), and paraquat (intracellular superoxide producer), which correlated with suppressed [glutamateex] elevations in the former two insults. Tolerance by preconditioning was reversed by manipulations that increased [glutamateex], such as by exposure to TBOA or GABAA receptor agonists during OGD, or by exposure to exogenous NMDA or glutamate. Pre-synaptic suppression of neuronal glutamate release by preconditioning, possibly via suppressed exocytic release, represents a key convergence point in neuroprotection during exposure to OGD and OGD-mimetics. © 2012 National Research Council Canada. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Publication date
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number21270115
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Record identifier0c2b3dd1-3d70-4c7f-9ae7-77b5f8958b09
Record created2014-01-03
Record modified2016-05-09
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