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dc.contributor.authorVermehren, Pen
dc.contributor.authorTrotman-Lucas, Men
dc.contributor.authorHechler, Ben
dc.contributor.authorGachet, Cen
dc.contributor.authorEvans, Ren
dc.contributor.authorGibson, Cen
dc.contributor.authorFern, Ren

<jats:p>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.</jats:p>

dc.format.extent30 - 47en
dc.titleCooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protectionen
dc.typeJournal Article
plymouth.organisational-group/Plymouth/Admin Group - REF
plymouth.organisational-group/Plymouth/Admin Group - REF/REF Admin Group - FoH
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
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plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
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dc.rights.embargoperiodNot knownen
rioxxterms.typeJournal Article/Reviewen
plymouth.funderIon homeostasis in optic nerve astrocytes::BBSRCen

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