title: Cross-tolerance to otherwise lethal N-methyl-D-aspartate and oxygen-glucose deprivation in preconditioned cortical cultures.
abstract: In vitro ischemic preconditioning induced by subjecting rat cortical cultures to nonlethal oxygen-glucose deprivation protects against a subsequent exposure to otherwise lethal oxygen-glucose deprivation. We provide evidence that attenuation of the postsynaptic N-methyl-D-aspartate (NMDA) receptor- and Ca(2+)-dependent neurotoxicity underlies oxygen-glucose deprivation tolerance. It is demonstrated that extended tolerance to otherwise lethal NMDA or oxygen-glucose deprivation can be induced by either of their sublethal forms of preconditioning. These four pathways are linked, since NMDA receptor blockade during preconditioning by oxygen-glucose deprivation eliminates tolerance. These results suggest that NMDA tolerance, induced by nonlethal activation of these receptors during oxygen-glucose deprivation preconditioning, underlies oxygen-glucose deprivation tolerance. Several neurotoxic downstream Ca(2+)-dependent signaling events specifically linked to NMDA receptor activation are attenuated during otherwise lethal oxygen-glucose deprivation in preconditioned cultures. Specifically, calpain activation, as well as degradation of microtubule-associated protein-2 and postsynaptic density-95, are attenuated 2 h following otherwise lethal NMDA treatment alone or oxygen-glucose deprivation in preconditioned cultures. Formation of microtubule-associated protein-2-labeled dendritic varicosities is also attenuated in preconditioned cultures within 1 h of lethal oxygen-glucose deprivation or NMDA application. Intracellular Ca(2+) levels, measured using the high- or low-affinity dyes Fluo-4 (K(d) approximately equal 345 nM) or Fluo-4FF (K(d) approximately equal 9.7 microM) respectively, are markedly attenuated during lethal oxygen-glucose deprivation in preconditioned cultures.Collectively, the results suggest the attenuation of the postsynaptic NMDA-mediated component of otherwise lethal oxygen-glucose deprivation through the suppression of Ca(2+)-dependent neurotoxic signaling, a mechanism that is initially induced by transient nonlethal activation of this receptor during ischemic preconditioning.
authors.affiliation: National Research Council of Canada, Institute for Biological Sciences, Ottawa, ON, Canada. joe.tauskela@nrc.ca
authors.forename: J S
authors.initials: JS
authors.lastname: Tauskela
authors.forename: T
authors.initials: T
authors.lastname: Comas
authors.forename: K
authors.initials: K
authors.lastname: Hewitt
authors.forename: R
authors.initials: R
authors.lastname: Monette
authors.forename: J
authors.initials: J
authors.lastname: Paris
authors.forename: M
authors.initials: M
authors.lastname: Hogan
authors.forename: P
authors.initials: P
authors.lastname: Morley
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D015415:Biomarkers; D002545:Brain Ischemia / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005947:Glucose / Q000494:pharmacology*; D019194:Ischemic Preconditioning; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D014966:Xanthenes
chemical_list: D000814:Aniline Compounds; D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; C409648:Fluo 4; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D014966:Xanthenes; C033652:postsynaptic density proteins; D016202:N-Methylaspartate; D002154:Calpain; D005947:Glucose; D010100:Oxygen; D002118:Calcium