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An electrophysiological evaluation of novel cognitive enhancers
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Springe, Signe (2020) An electrophysiological evaluation of novel cognitive enhancers. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3761234
Abstract
The collection of studies presented in this thesis evaluates novel therapeutics and assesses their potential as cognitive enhancers. The study also examines the impact of ambient glucose levels on a widely used cellular model for learning and memory. Finally, the work described here explores a possible mechanism of action of an experimental nootropic compound. Taken together, this thesis aims to address the prevailing public health threat of cognitive decline by expanding the existing knowledge on nootropics and on the effects of glucose on learning and memory.
1. The validity of a L-436, a novel and potentially beneficial positive allosteric modulator (PAM) of α7 nAChRs, developed by Merck, was assessed via the application of the extracellular recording electrophysiology technique. The effectiveness of L-436 was compared with known modulators of these receptors: a partial agonist, EVP-6124 and a PAM BNC-375. The key findings from this study are that L-436 induced a concentration-dependent enhancement of LTP in both mouse and rat hippocampal slices. This effect was not present in mice lacking α7 nAChRs (Acrα7- mice) unlike their wild-type littermates. In rat hippocampal slices, the maximum effect of L-456 on LTP, observed around a concentration of 10 μM, was inhibited in the presence of the selective α7 nAChR antagonist MLA. Consequently, these data suggest that L-436 enhances LTP via a direct effect on α7 nAChRs. Therefore, the effects of L-436 on LTP are similar those of established partial agonists of α7 nAChRs such as EVP-6124, GTS-21, S 24795 and SSR180711.
2. The second study evaluated the effects of three different ambient D-glucose concentrations (10, 5 and 2 mM) on theta-burst-induced LTP, in the presence of either vehicle or a selection of adenosine receptor-targeting antagonists with the aim to elucidate the role of adenosine receptors in LTP. It was also of interest to investigate the influence of extracellular D-glucose on LTP due to the well-known disparity between extracellular glucose concentration in vitro, as opposed to in vivo conditions. Data presented here suggest little effect of extracellular glucose on LTP and does not support the idea that ambient extracellular glucose levels impact LTP via a glial-adenosine-dependent mechanism as is observed in hypothalamus.
3. The aim of the third study was to provide an insight into the mechanism of action SD118, novel putative cognition-enhancing compound developed by SyndesI, using Levetiracetam as the scaffold structure. By using whole-cell patch clamp recording techniques in hippocampal slices SD118 was shown to enhance excitatory glutamatergic synaptic transmission in the hippocampus in a frequency-dependent manner. Excitatory synaptic responses were little affected at low frequencies of stimulation (0.1 to 2 Hz) but were potentiated at higher frequencies (10 and 20 Hz). Therefore, SD118 shares the frequency-dependent effect on excitatory synaptic transmission with Levetiracetam, albeit with different outcomes. Unlike Levetiracetam, SD118 enhances synaptic transmission and could therefore be beneficial for cognitive enhancement.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
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Official Date: | 2020 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Spanswick, David C. | ||||
Sponsors: | NeuroSolutions Ltd. | ||||
Format of File: | |||||
Extent: | xxii, 255 leaves : illustrations | ||||
Language: | eng |
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