Ischaemic stroke initiates pathological mechanisms that contribute to injury. Despite significant research into this area available clinical treatments are limited, highlighting the need for continued research to identify novel therapeutic targets. Previously, pre-clinical NMDA receptor antagonists have demonstrated neuroprotection, yet they have failed to translate at clinical trial. Both Glutamate and ATP release are key contributors to excitotoxic injury following stroke, therefore it is rational to consider the possibility of multi-pathway targeting as a potential neuroprotective strategy. The aim of this project was to investigate the use of the current clinically available NMDA receptor antagonist, Memantine Hydrochloride, alone and in combination with a ubiquitous P2 receptor antagonist, PPADS, within an in vitro and in vivo model of ischaemia. An in vitro neural-glial co-culture was exposed to oxygen-glucose deprivation. Memantine exacerbated cell death at high concentrations, and significantly reduced cell death at low concentrations. P2 receptor inhibition also significantly reduced in vitro cell death. Furthermore, combined low concentration treatment further enhanced the protective effect of both antagonists in vitro. However, this was not shown following treatment in vivo. Sustained mini pump Memantine administration at a therapeutic dose significantly increased infarct volume following middle cerebral artery occlusion in vivo. These results may have important implications for the selection of Memantine doses in Alzheimer’s disease patients that may also experience an ischaemic episode. This study provides evidence that low dose combined targeting of glutamatergic and purinergic excitotoxicity produces neuroprotection following in vitro ischaemia, providing a novel therapeutic target for ischaemia research. This supports the concept of combined NMDA and P2 receptor targeting as a potential therapeutic target for stroke. This study also provides evidence that Memantine exhibits a toxic action in vitro and in vivo, questioning the current use of the drug and its potential to exacerbate stroke injury.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634411 |
| Date | January 2015 |
| Creators | Trotman, Melissa Elizabeth |
| Contributors | Gibson, Claire; Fern, Robert |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/31404 |
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