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Neuroglia 2018, 1(1), 5; https://doi.org/10.3390/neuroglia1010005

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

1
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9BH, UK
2
Department of Neuroscience, Psychology & Behaviour, University of Leicester, Leicester LE1 9BH, UK
3
UMR_S949, Institut National de la Santé et de la Recherche Médicale (INSERM), F-67065 Strasbourg, France
4
Établissement Français du Sang-Alsace (EFS-Alsace), F-67065 Strasbourg, France
5
Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9BH, UK
6
Peninsula School of Medicine and Dentistry, University of Plymouth, John Bull Building, Research Way, Plymouth PL6 8BU, UK
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 13 February 2018 / Revised: 6 March 2018 / Accepted: 8 March 2018 / Published: 14 March 2018
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Abstract

Excitotoxicity is the principle mechanism of acute injury during stroke. It is defined as the unregulated accumulation of excitatory neurotransmitters such as glutamate within the extracellular space, leading to over-activation of receptors, ionic disruption, cell swelling, cytotoxic Ca2+ elevation and a feed-forward loop where membrane depolarisation evokes further neurotransmitter release. Glutamate-mediated excitotoxicity is well documented in neurons and oligodendrocytes but drugs targeting glutamate excitotoxicity have failed clinically which may be due to their inability to protect astrocytes. Astrocytes make up ~50% of the brain volume and express high levels of P2 adenosine triphosphate (ATP)-receptors which have excitotoxic potential, suggesting that glutamate and ATP may mediate parallel excitotoxic cascades in neurons and astrocytes, respectively. Mono-cultures of astrocytes expressed an array of P2X and P2Y receptors can produce large rises in [Ca2+]i; mono-cultured neurons showed lower levels of functional P2 receptors. Using high-density 1:1 neuron:astrocyte co-cultures, ischemia (modelled as oxygen-glucose deprivation: OGD) evoked a rise in extracellular ATP, while P2 blockers were highly protective of both cell types. GluR blockers were only protective of neurons. Neither astrocyte nor neuronal mono-cultures showed significant ATP release during OGD, showing that cell type interactions are required for ischemic release. P2 blockers were also protective in normal-density co-cultures, while low doses of combined P2/GluR blockers where highly protective. These results highlight the potential of combined P2/GluR block for protection of neurons and glia. View Full-Text
Keywords: astrocyte; ATP; excitotoxicity; glutamate; NMDA; neuron; P-2 receptor; stroke astrocyte; ATP; excitotoxicity; glutamate; NMDA; neuron; P-2 receptor; stroke
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Vermehren, P.; Trotman-Lucas, M.; Hechler, B.; Gachet, C.; Evans, R.J.; Gibson, C.L.; Fern, R. Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection. Neuroglia 2018, 1, 5.

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