title: Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults.
abstract: Preconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateex) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateex elevations, thereby identifying a 'ceiling' to neuroprotection. Neuroprotective 'rescue' of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateex rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateex suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateex suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateex levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, 'stress-testing' against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateex levels, thereby 'buying time' for acute anti-excitotoxic pharmacologic rescue.
authors: Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
authors: Joseph S
authors: JS
authors: Tauskela
authors: Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
authors: Amy
authors: A
authors: Aylsworth
authors: Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
authors: Melissa
authors: M
authors: Hewitt
authors: Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
authors: Eric
authors: E
authors: Brunette
authors: Université de Nice Sophia Antipolis, IPMC, Sophia Antipolis, F-06560, France; CNRS, IPMC, Sophia Antipolis, F-06560, France. Electronic address: blondeau@ipmc.cnrs.fr.
authors: Nicolas
authors: N
authors: Blondeau
mesh_terms: D015761:4-Aminopyridine; D000818:Animals; D001224:Aspartic Acid; D001640:Bicuculline; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D018920:Coculture Techniques; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D019194:Ischemic Preconditioning / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010042:Ouabain; D051381:Rats; D020521:Stroke; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D010042:Ouabain; D016291:Dizocilpine Maleate; D015761:4-Aminopyridine; D005947:Glucose; D001640:Bicuculline
keywords: 2-Deoxyglucose (Pubmed CID: 24894205); 4-Aminopyridine (Pubmed CID: 1727); Bicuculline (Pubmed CID: 104871); Desferoxamine ((Pubmed CID: 24894304); Diazoxide (Pubmed CID: 3019); Dimethyloxallyl glycine (Pubmed CID: 560326); Excitotoxicity; Ischemia; Lovastatin (Pubmed CID: 16760544); N-Methyl-d-aspartate (Pubmed CID: 22880); NMDA receptor; Neuroprotection; Preconditioning; Tolerance; Tunicamycin (Pubmed CID: 16760689)