Acidosis enhances toxicity induced by kainate and zinc exposure in aged cultured astrocytes.
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 Zn(2+) 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 Zn(2+), 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 Zn(2+). Astrocytes exposed to 1 mM kainate for 1 h did not exhibit any degeneration in the following 24 h, and addition of 50 microM Zn(2+) 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/Zn(2+) exposure performed under acidotic conditions. We found that the combination of 1 h exposure to 1 mM kainate + 50 microM Zn(2+) at pH 6.2 produced a strong increase in intracellular free Zn(2+) ([Zn(2+)](i)), and extensive glial injury. Comparing [Zn(2+)](i) rises triggered by kainate/Zn(2+) exposure at pH 7.4 or pH 6.2 we found that acidosis promotes increased toxic [Zn(2+)](i) levels as a result of a lethal combination of both enhanced Zn(2+) influx through Zn(2+) permeable AMPA/kainate channels and impaired intracellular buffering of the cation.
Sensi
Stefano L
SL
Department of Neurology, Molecular Neurology Unit, CeSI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, 66013, Italy. ssensi@uci.edu
Rockabrand
Erica
E
Canzoniero
Lorella M T
LM
D000138:Acidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists / Q000378:metabolism; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D015032:Zinc