The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease
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 n...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2022
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| Online Access: | https://eprints.nottingham.ac.uk/69163/ |
| _version_ | 1848800540663742464 |
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| author | Kaur, Kiran |
| author_facet | Kaur, Kiran |
| author_sort | Kaur, Kiran |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:53:11Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-69163 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:53:11Z |
| publishDate | 2022 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-691632025-02-28T15:15:22Z https://eprints.nottingham.ac.uk/69163/ The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease Kaur, Kiran 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. 2022-07-31 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en cc_by https://eprints.nottingham.ac.uk/69163/1/10004682%20KK%20the%20effect%20of%20alkaloids%20on%20NMDAR%20neurotransmission.pdf 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. Alzheimer’s disease NMDA receptor function |
| spellingShingle | Alzheimer’s disease NMDA receptor function Kaur, Kiran The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title | The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title_full | The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title_fullStr | The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title_full_unstemmed | The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title_short | The effect of memantine and the ladybird alkaloid, harmonine, on NMDA receptor function and Alzheimer’s disease |
| title_sort | effect of memantine and the ladybird alkaloid, harmonine, on nmda receptor function and alzheimer’s disease |
| topic | Alzheimer’s disease NMDA receptor function |
| url | https://eprints.nottingham.ac.uk/69163/ |