Xenon is a general anaesthetic gas with neuroprotective properties. Inhibition of the N-methyl-D-aspartate (NMDA) receptor glycine co-agonist site has been shown to mediate xenon neuroprotection against ischemic injury in vitro. Site-directed mutagenesis was used to produce point mutations in the GluN1 subunit of rat NMDA receptors. These were then expressed in HEK293 cells and the responses of mutant GluN1/GluN2A receptors to glycine and anaesthetics assessed using patch-clamp electrophysiology. Two mutations of the phenylalanine 758 site were found to eliminate xenon binding to the receptor without altering glycine affinity or the binding of sevoflurane and isoflurane. These selective mutations will allow for knock-in animals to be used to dissect the mechanism(s) underlying xenon neuroprotection and anaesthesia in vivo. The ability of the other noble gases (helium, neon, argon, and krypton) to influence two known molecular targets of xenon - the NMDA receptor and the TREK-1 channel - was also assessed using patch-clamp electrophysiology. These were found to have no influence on either NMDA receptors or TREK-1 channels. Finally, xenon's neuroprotective efficacy against traumatic brain injury (TBI) in vivo was assessed using the rodent controlled cortical impact model of TBI. Focal contusion injury was administered to male C57 mice and animals administered either 75% xenon or control treatment for three hours. Xenon-treated animals performed better in functional tests and displayed favourable outcomes in brain histology, as compared to control animals. This data provides the first evidence of a neuroprotective effect for xenon against TBI in vivo.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:656627 |
| Date | January 2014 |
| Creators | Armstrong, Scott |
| Contributors | Dickinson, Robert; Franks, Nicholas |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/24766 |
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