title: Reduced extracellular zinc levels facilitate glutamate-mediated oligodendrocyte death after trauma.
abstract: Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor-κB transcription factor in astrocytes reduces white matter damage and improves functional recovery following spinal cord injury. In the current study, we demonstrate that activation of the nuclear factor-κB transcription factor within astrocytes results in a significant increase in oligodendrocyte death following trauma by reducing extracellular zinc levels and inducing glutamate excitotoxicity. By using an ionotropic glutamate receptor antagonist (CNQX), we show that astroglial nuclear factor-κB-mediated oligodendrocyte death is dependent on glutamate signaling despite no change in extracellular glutamate concentrations. Further analysis demonstrated a reduction in levels of extracellular zinc in astrocyte cultures with functional nuclear factor-κB signaling following trauma. Cotreatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity under low-zinc conditions, suggesting that the presence of zinc at specific concentrations can prevent glutamate excitotoxicity. These studies demonstrate a novel role for zinc in regulating oligodendrocyte excitotoxicity and identify new therapeutic targets to prevent oligodendrocyte cell death in central nervous system trauma and disease.
authors.affiliation: The Miami Project To Cure Paralysis, University of Miami, Miami, Florida 33136, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Johnstone
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.forename: Arumugam R
authors.initials: AR
authors.lastname: Jayakumar
authors.forename: Valerie
authors.initials: V
authors.lastname: Bracchi-Ricard
authors.forename: Erik
authors.initials: E
authors.lastname: Runko
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Liebl
authors.forename: Michael D
authors.initials: MD
authors.lastname: Norenberg
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000737:chemistry* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D018698:Glutamic Acid; D015032:Zinc
references.citation: Biometals. 2001 Sep-Dec;14(3-4):353-66
references.pmid: 11831465
references.citation: J Biol Chem. 1995 Feb 10;270(6):2473-7
references.pmid: 7852308
references.citation: Biochim Biophys Acta. 2006 Jul;1763(7):711-22
references.pmid: 16675045
references.citation: Ann Neurol. 2003 May;53(5):588-95
references.pmid: 12730992
references.citation: Neuroscience. 1999 Mar;89(1):175-82
references.pmid: 10051227
references.citation: J Exp Med. 2005 Jul 4;202(1):145-56
references.pmid: 15998793
references.citation: Nature. 1996 Oct 24;383(6602):716-9
references.pmid: 8878481
references.citation: J Neurosci. 2000 Feb 1;20(3):1190-8
references.pmid: 10648723
references.citation: J Neurophysiol. 2002 Sep;88(3):1245-51
references.pmid: 12205145
references.citation: Neurosci Biobehav Rev. 1997 Mar;21(2):151-66
references.pmid: 9062938
references.citation: J Neurotrauma. 2004 Jun;21(6):754-74
references.pmid: 15253803
references.citation: J Neurochem. 2008 Oct;107(1):1-19
references.pmid: 18643793
references.citation: Brain Res. 1991 May 3;547(2):344-8
references.pmid: 1884213
references.citation: Cell Mol Biol (Noisy-le-grand). 2000 Jun;46(4):797-806
references.pmid: 10875441
references.citation: J Neurosci. 1997 Feb 1;17(3):1055-63
references.pmid: 8994060
references.citation: Annu Rev Nutr. 2004;24:151-72
references.pmid: 15189117
references.citation: N Engl J Med. 1994 Mar 3;330(9):613-22
references.pmid: 7905600
references.citation: J Biol Chem. 2001 Jun 22;276(25):22258-64
references.pmid: 11301334
references.citation: J Neurochem. 2009 Jul;110(2):765-78
references.pmid: 19522780
references.citation: Brain Res. 2005 Mar 15;1038(1):92-9
references.pmid: 15748877
references.citation: Brain Res Mol Brain Res. 1994 Mar;22(1-4):144-50
references.pmid: 8015375
references.citation: Cell. 1991 Oct 4;67(1):11-9
references.pmid: 1717158
references.citation: Neuroscience. 1999;93(4):1383-9
references.pmid: 10501463
references.citation: Eur J Neurosci. 1999 Jan;11(1):327-34
references.pmid: 9987035
references.citation: J Neurosci. 1997 Dec 15;17(24):9554-64
references.pmid: 9391010
references.citation: Trends Biochem Sci. 2005 Jan;30(1):43-52
references.pmid: 15653325
references.citation: J Neurosci. 1999 Jul 15;19(14):5711-20
references.pmid: 10407012
references.citation: J Neuroinflammation. 2011 Aug 03;8:89
references.pmid: 21812954
references.citation: Trends Neurosci. 2000 Aug;23(8):365-71
references.pmid: 10906800
references.citation: J Neurosci. 1998 Apr 1;18(7):2321-34
references.pmid: 9502793
references.citation: J Surg Res. 1991 Nov;51(5):417-24
references.pmid: 1758175
references.citation: Brain Res. 1988 Apr 19;446(2):383-6
references.pmid: 3370496
references.citation: Exp Neurol. 2003 Jul;182(1):35-48
references.pmid: 12821375
references.citation: Neuroscience. 2001;103(1):203-18
references.pmid: 11311801
references.citation: Brain Res. 2000 Dec 15;886(1-2):99-107
references.pmid: 11119691
references.citation: Nat Neurosci. 2004 Oct;7(10):1088-95
references.pmid: 15452578
references.citation: Science. 1984 Dec 14;226(4680):1345-7
references.pmid: 6095454
references.citation: Exp Neurol. 1999 Oct;159(2):538-44
references.pmid: 10506525
references.citation: Glia. 2004 Nov 1;48(2):145-55
references.pmid: 15378655
references.citation: Brain Res. 1990 Oct 29;531(1-2):318-21
references.pmid: 1963103
references.citation: J Neurosurg. 1976 Nov;45(5):521-34
references.pmid: 972336
references.citation: J Neurosci Res. 1988 Jul;20(3):291-303
references.pmid: 2852260
references.citation: J Neuropathol Exp Neurol. 2008 May;67(5):417-27
references.pmid: 18431255
references.citation: Neuroscience. 2001;104(1):235-51
references.pmid: 11311546
references.citation: Trends Pharmacol Sci. 1998 Aug;19(8):328-34
references.pmid: 9745361
references.citation: Neuron. 1993 Jan;10(1):43-9
references.pmid: 7678965
references.citation: Pflugers Arch. 2004 Feb;447(5):796-800
references.pmid: 12748861
references.citation: Neurosci Lett. 1990 Feb 16;109(3):247-52
references.pmid: 2330128
references.citation: J Neurosci. 1998 May 1;18(9):3251-60
references.pmid: 9547234
references.citation: J Neurosci. 1997 Jul 15;17(14):5395-406
references.pmid: 9204923
references.citation: Spine (Phila Pa 1976). 2000 Jul 15;25(14):1859-66
references.pmid: 10888960
references.citation: J Biol Chem. 2000 Feb 25;275(8):5560-4
references.pmid: 10681536