Rehman, Abdul
(2023)
Effect of memantine on rat and human NMDA receptors in comparison with harmonia axyridis extract.
MRes thesis, University of Nottingham.
Abstract
Alzheimer's disease results in neuronal cell death, accumulation of amyloid-beta plaques, hyperphosphorylation of tau proteins, and ultimately, impairment of memory. Due to excessive glutamate in the synaptic cleft, NMDA receptor-dependent neurotransmission may be upregulated resulting in an excessive influx of Ca2+ ions causing excitotoxicity. Currently, memantine is the only drug approved by the FDA targeting NMDA receptor-mediated excitotoxicity. NMDA receptors consist of combinations of two GluN1 and GluN2 subunits forming a hetero-tetrameric structure.
The purpose of this research was to analyze species-specific effects of memantine inhibition between humans and earlier research performed on rat NMDA receptors containing GluN1-1a subunits with GluN2A. We also compared the inhibition by an alkaloid extract from harlequin ladybirds containing 90% harmony (HAE), and memantine on human NMDA clones and the earlier performed experiments on rat clones. NMDA receptors were expressed in Xenopus oocytes and a two-electrode voltage clamp was used to measure responses to NMDA + glycine in the absence and presence of HAE and memantine. The IC50 for memantine inhibition of rat GluN11a/GluN2A at holding potentials of -50mV, -75mV, and -100mV were 4.19μM, 1.45μM, and 1.84μM, respectively. The IC50 for memantine at the same holding potentials in humanGluN11a/GluN2A were 3.4μM, 1.20μM, and 0.7μM respectively. The IC50 for HAE inhibition of rat GluN1-1a/GluN2A at these holding potentials were 2.65μg/mL, 1.11μg/mL, and 1.75μg/mL, respectively. Whereas the IC50 value for HAE inhibition of humanGluN1-GluN2a was 2.50μg/mL (8.80μM), 1.46μg/mL (5.16μM), and 0.86μg/mL (3.06μM), respectively.
In conclusion, memantine is effective at inhibiting human and rat NMDA receptors. Moreover, harmonine in HAE inhibits NMDA receptors with a similar mode of action as memantine. Memantine and HAE both showed voltage dependence inhibition. Moreover, the inhibition of HAE and memantine of NMDA receptors in rats and human NMDARs subtypes (GluN1-GluN2A) showed similarity in the terms of inhibition.
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