Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling: Am J Physiol Cell Physiol

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Journal titleAm J Physiol Cell Physiol
Subject2,4-Dinitrophenol; ACID; Animals; Anoxia; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Canada; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cells,Cultured; Cerebral Cortex; CHLORIDE; deficiency; Extracellular Space; Glucose; Glutamic Acid; INHIBITOR; INHIBITORS; Ischemic Preconditioning; metabolism; Mitochondria; MODEL; N-Methylaspartate; Neurons; Neurotoxins; pathology; PATHWAY; PATHWAYS; pharmacology; physiopathology; POTENT; POTENTIAL; protein; Rats; Rats,Sprague-Dawley; Reactive Oxygen Species; receptor; Role; Signal Transduction; Support,Non-U.S.Gov't; TARGET; Uncoupling Agents
AbstractTransient exposure of rat cortical cultures to nonlethal oxygen-glucose deprivation (OGD preconditioning) induces tolerance to otherwise lethal oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate 24 h later. This study evaluates the role of cytosolic and mitochondrial Ca2+-dependent cellular signaling. Mechanistic findings are placed in context with other models of ischemic preconditioning or known neurotoxic pathways within cortical neurons. Tolerance to otherwise lethal OGD is suppressed by performing OGD preconditioning in the presence of the broad-scope catalytic antioxidants Mn(III)tetra(4-carboxyphenyl)porphyrin (MnTBAP) or Zn(II)tetra(4-carboxyphenyl)porphyrin [Zn(II)TBAP], but not by a less active analog, Mn(III)tetra(4-sulfonatophenyl)porphyrin, or a potent superoxide scavenger, Mn(III)tetra(N-ethyl-2-pyridyl)porphyrin chloride. Inhibitors of adenosine A1 receptors, nitric oxide synthase, mitogen-activated protein kinase, and poly(ADP-ribose) polymerase fail to suppress OGD preconditioning despite possible links with reactive oxygen species in other models of ischemic preconditioning. Preconditioning is suppressed by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), which has been ascribed elsewhere to inhibition of superoxide transport to the cytosol through mitochondrial anion channels. However, although it induces mitochondrial Ca2+ uptake, neuronal preconditioning is largely insensitive to mitochondrial uncoupling with carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone or 2,4-dinitrophenol. Un-couplers will prevent production of mitochondrial reactive oxygen species, implying nonmitochondrial targets by MnTBAP, Zn(II)TBAP, and DIDS. Emphasizing the importance of an increase in cytosolic Ca2+ during preconditioning, a Ca2+/calmodulin-dependent protein kinase II inhibitor, KN-62, suppresses development of subsequent tolerance. Summarizing, only those cellular transduction pathways that have the potential to be neurotoxic may be activated by preconditioning in cortical neurons. Finally, a marked decrease in extracellular glutamate is observed during otherwise lethal OGD in preconditioned cultures, suggesting that this end effector may represent a point of convergence across different preconditioning models
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AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberTAUSKELA2003
NPARC number9371179
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Record identifier6c7d30c3-7d6e-476b-a700-03d3e102a454
Record created2009-07-10
Record modified2016-05-09
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