Abstract
A key feature of cerebral ischemia, one of the leading causes of death associated with ageing, is excessive accumulation of glutamate in the synaptic cleft. In some forms of cerebral ischemia, like transient global ischemia, high levels or synaptic glutamate are complemented by a concomitant increase in extracellular Zn2+ as result of the release of the cation that is present in the pre-synaptic vesicles of glutamatergic neurons. Interestingly, while neurons are very sensitive to the toxicity triggered by exposure to either glutamate or Zn2+, astrocytes show less vulnerability to these toxins. We examined the vulnerability of cortical type 1 astrocytes to a combined exposure to the AMPA/kainate receptor agonist kainate and Zn2+. Astrocytes exposed to 1 mM kainate for 1 h did not exhibit any degeneration in the following 24 h, and addition of 50 μM Zn2+ to the kainate exposure failed to produce any further glial loss. Another hallmark of cerebral ischemia is parechymal acidosis and therefore, we tested the susceptibility of our cultured astrocytes to a kainate/Zn2+ exposure performed under acidotic conditions. We found that the combination of 1 h exposure to 1 mM kainate + 50 μM Zn2+ at pH 6.2 produced a strong increase in intracellular free Zn2+ ([Zn2+]i), and extensive glial injury. Comparing [Zn2+]i rises triggered by kainate/Zn2+ exposure at pH 7.4 or pH 6.2 we found that acidosis promotes increased toxic [Zn2+]i levels as a result of a lethal combination of both enhanced Zn2+ influx through Zn2+ permeable AMPA/kainate channels and impaired intracellular buffering of the cation.
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Abbreviations
- AMPA:
-
α-amino3–hydroxy-5-methyl-4-isoxazolepropionic-acid
- Ca-A/K channels:
-
Ca2+-permeable AMPA/kainate channels
- LDH:
-
lactate dehydrogenase
- NMDA:
-
N-methyl-D-aspartate
- VSCC:
-
voltage sensitive Ca2+ channels
- TPEN:
-
N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine.
References
Aizenman E, Stout AK, Hartnett KA, Dineley KE, McLaughlin B, Reynolds IJ (2000) Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J Neurochem 75:1878–1888
Arslan P, Di Virgilio F, Beltrame M, Tsien RY, Pozzan T (1985) Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J Biol Chem 260:2719–2727
Busa WB, Nuccitelli R (1984) Metabolic regulation via intracellular pH. Am J Physiol 246:R409–438
Chesler M (2003) Regulation and modulation of pH in the brain. Physiol Rev 83:1183–1221
Choi DW, Maulucci-Gedde M, Kriegstein AR (1987) Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368
David JC, Yamada KA, Bagwe MR, Goldberg MP (1996) AMPA receptor activation is rapidly toxic to cortical astrocytes when desensitization is blocked. J Neurosci 16:200–209
Dineley KE, Scanlon JM, Kress GJ, Stout AK, Reynolds IJ (2000) Astrocytes are more resistant than neurons to the cytotoxic effects of increased [Zn(2+)](i). Neurobiol Dis 7:310–320
Dineley KE, Brocard JB, Reynolds IJ (2002) Elevated intracellular zinc and altered proton homeostasis in forebrain neurons. Neuroscience 114:439–449
Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462
Friede RL, Van Houten WH (1961) Relations between postmortem alterations and glycolytic metabolism in the brain. Exp Neurol 4:197–204
Giffard RG, Monyer H, Christine CW, Choi DW (1990) Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506:339–342
Hillered L, Ernster L, Siesjo BK (1984) Influence of in vitro lactic acidosis and hypercapnia on respiratory activity of isolated rat brain mitochondria. J Cereb Blood Flow Metab 4:430–437
Jeng J-M, Jia Y, Bonanni L, Weiss JH (2002) Divergent effects of pH on Zn2+ and Ca2+ flux through Ca2+-permeable AMPA/kainate channels (CAKR). In: SFN Annual Meeting, Online Edition, p. 539. Orlando, FL: Washington, DC: Society for Neuroscience
Jiang LJ, Vasak M, Vallee BL, Maret W (2000) Zinc transfer potentials of the alpha - and beta-clusters of metallothionein are affected by domain interactions in the whole molecule. Proc Natl Acad Sci USA 97:2503–2508
Kerchner G, Canzoniero L, Yu S, Ling C, Choi DW (2000) Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones. J Physiol 528:39–52
Koh JY, Goldberg MP, Hartley DM, Choi DW (1990) Non-NMDA receptor-mediated neurotoxicity in cortical culture. J Neurosci 10:693–705
Kraig RP, Chesler M (1990) Astrocytic acidosis in hyperglycemic and complete ischemia. J Cereb Blood Flow Metab 10:104–114
Lin DD, Cohen AS, Coulter DA (2001) Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons. J Neurophysiol 85:1185–1196
Lipton SA (2006) NMDA receptors, glial cells, and clinical medicine. Neuron 50:9–11
McLaughlin B, Pal S, Tran MP, Parsons AA, Barone FC, Erhardt JA, Aizenman E (2001) p38 Activation is required upstream of potassium current enhancement and caspase cleavage in thiol oxidant-induced neuronal apoptosis. J Neurosci 21:3303–3311
Mocchegiani E, Giacconi R, Fattoretti P, Casoli T, Cipriano C, Muti E, Malavolta M, DiStefano G, Bertoni-Freddari C (2004) Metallothionein isoforms (I+II and III) and interleukin-6 in the hippocampus of old rats: may their concomitant increments lead to neurodegeneration? Brain Res Bull 63:133–142
Rothman S (1984) Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 4:1884–1891
Sensi SL, Canzoniero LM, Yu SP, Ying HS, Koh JY, Kerchner GA, Choi DW (1997) Measurement of intracellular free zinc in living cortical neurons: routes of entry. J Neurosci 17:9554–9564
Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR, Kaczmarek LK, Weiss JH (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci USA 100:6157–6162
Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH (1999) Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci USA 96:2414–2419
Siesjo BK, Bendek G, Koide T, Westerberg E, Wieloch T (1985) Influence of acidosis on lipid peroxidation in brain tissues in vitro. J Cereb Blood Flow Metab 5:253–258
Yokoyama M, Koh J, Choi DW (1986) Brief exposure to zinc is toxic to cortical neurons. Neurosci Lett 71:351–355
Yu SP, Canzoniero LM, Choi DW (2001) Ion homeostasis and apoptosis. Curr Opin Cell Biol 13:405–411
Acknowledgements
We thank Tiziana D’Ettorre and Francesca Faricelli for expert assistance with cell cultures. This work was supported by PRIN 2004, FIRB 2003 (SLS).
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Presented at the ZincAge Conference, Madrid, February 10–13, 2006.
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Sensi, S.L., Rockabrand, E. & Canzoniero, L.M.T. Acidosis enhances toxicity induced by kainate and zinc exposure in aged cultured astrocytes. Biogerontology 7, 367–374 (2006). https://doi.org/10.1007/s10522-006-9051-9
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DOI: https://doi.org/10.1007/s10522-006-9051-9