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Kaur, Kiran (2022) The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease. MRes thesis, University of Nottingham.

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Abstract

Alzheimer’s disease (AD) is the most common late onset form of dementia. N-methyl-D-aspartate (NMDA) receptors are excitatory glutamate receptors and are primary therapeutic targets due to their glutamate and glycine recognition sites. Excessive glutamate neurotransmission can ultimately result in neuronal cell death, potentially leading to AD pathological conditions. Current treatments of AD include N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine and acetylcholine receptor inhibitors. In the first part of this study, clinical trials of memantine were examined to assess whether memantine had a positive or negative effect on the pathological symptoms of AD human patients. The results suggested that memantine has a positive effect on the following outcome measures: molecular biomarkers and imaging; cognition and behaviour; functional and linguistic communication. The most common dose used was 20 mg of memantine per day. The highest dose of 28 mg was found to have a more significant positive effect on AD patient symptoms compared to lower doses of 10-20 mg. From this, it was concluded that memantine has a therapeutic effect on AD patient symptoms.

In addition, a two-electrode voltage clamp was used to assess the effects of the memantine and Harmonia axyridis alkaloid extract (HAE) on NMDA receptors expressed in Xenopus laevis oocytes. Memantine and HAE were found to inhibit the NMDA receptor in a concentration-dependent manner. Furthermore, memantine was shown to inhibit NMDA receptor responses in GluN1-1a/GluN2A and GluN1-1a/GluN2B receptor subtypes in a voltage-dependent manner. The highest concentration of HAE only partially blocked the NMDA receptor whilst the memantine applied at the highest concentration demonstrated complete inhibition of NMDA receptor responses. IC50 values were shown to be lowest at -75 mV compared to the more negative holding potential of -100 mV. This was found for all subunits except the GluN1-1a/GluN2B subunit combination when HAE was applied. Overall, memantine and harmonine were found to show high levels of inhibition of NMDA receptor response at highest concentrations in both receptor subunits.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Mellor, Ian Knight, Helen
Keywords:	Alzheimer’s disease, NMDA receptor function
Subjects:	R Medicine > RC Internal medicine > RC 321 Neuroscience. Biological psychiatry. Neuropsychiatry
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	69163
Depositing User:	Kaur, Kiran
Date Deposited:	31 Jul 2022 04:42
Last Modified:	01 Aug 2022 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/69163

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