O'Hare Doig, Ryan L and Bartlett, Carole A and Smith, Nicole M and Hodgetts, Stuart I and Dunlop, Sarah A and Hool, Livia C and Fitzgerald, Melinda (2016) Specific combinations of Ca(2+) channel inhibitors reduce excessive Ca(2+) influx as a consequence of oxidative stress and increase neuronal and glial cell viability in vitro. Neuroscience, 339. pp.450-462. ISSN 1873-7544 (PP OA)
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Abstract
Combinations of Ca(2+) channel inhibitors have been proposed as an effective means to prevent excess Ca(2+) flux and death of neurons and glia following neurotrauma in vivo. However, it is not yet known if beneficial outcomes such as improved viability have been due to direct effects on intracellular Ca(2+) concentrations. Here, the effects of combinations of Lomerizine (Lom), YM872, memantine and/or oxATP to block voltage gated Ca(2+) channels, Ca(2+) permeable AMPA receptors, NMDA receptors and purinergic P2X7 receptors (P2X7R) respectively, on Ca(2+) concentration and viability of primary mixed cortical cultures exposed to hydrogen peroxide (H2O2) insult, were assessed. The contribution of Ryanodine sensitive intracellular stores to intracellular Ca(2+) concentration was also assessed. Live cell calcium imaging revealed that a 30 minute H2O2 insult induced a slow increase in intracellular Ca(2+), in part from intracellular sources, associated with loss of cell viability by 6 hours. Most combinations of inhibitors that included oxATP significantly decreased Ca(2+) influx and increased cell viability when administered simultaneously with H2O2. However, reductions in intracellular Ca(2+) concentration were not always linked to improved cell viability. Examination of the density of specific cell subpopulations demonstrated that most combinations of inhibitors that included oxATP preserved NG2+ non-oligodendroglial cells, but preservation of astrocytes and neurons required additional inhibitors. Olig2(+) oligodendroglia and ED-1(+) activated microglia/macrophages were not preserved by any of the inhibitor combinations. These data indicate that following H2O2 insult, limiting intracellular Ca(2+) entry via P2X7R is generally associated with increased cell viability. Protection of NG2+ non-oligodendroglial cells by Ca(2+) channel inhibitor combinations may contribute to observed beneficial outcomes in vivo.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 14 Oct 2016 04:43 |
| Last Modified: | 15 Jan 2018 02:03 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/499 |
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