title: Preconditioning induces tolerance by suppressing glutamate release in neuron culture ischemia models.
abstract: This 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 Ca(2+) (Ca(2+) 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.
authors.affiliation: National Research Council Canada, Ottawa, Ontario, Canada. joe.tauskela@nrc-cnrc.gc.ca
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tauskela
authors.forename: Amy
authors.initials: A
authors.lastname: Aylsworth
authors.forename: Melissa
authors.initials: M
authors.lastname: Hewitt
authors.forename: Eric
authors.initials: E
authors.lastname: Brunette
authors.forename: Geoffrey A R
authors.initials: GA
authors.lastname: Mealing
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D048429:Cell Size; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors; D005260:Female; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D019194:Ischemic Preconditioning / Q000379:methods*; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D018079:Receptors, GABA / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D017382:Reactive Oxygen Species; D018079:Receptors, GABA; D017661:Receptors, Presynaptic; C493395:Slc1a2 protein, rat; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D015032:Zinc; D002118:Calcium