Ischemic strokes are a major cause of death and disability, yet efficacious pharmacotherapies remain limited. Although neuronal cell death during stroke is primarily induced via excessive Ca2+ influx through NMDARs following overactivation by uncontrolled glutamate release, antagonism of these receptors has been shown to be ineffective due to intolerable side effects. This thesis highlights a novel therapeutic strategy for stroke wherein NMDAR-mediated excitotoxicity is temporarily and dynamically mitigated via the initiation of a process termed “glycine induced NMDAR internalization” (GINI). While GINI occurs in vitro following application of high doses of glycine, achieving these levels of glycine in vivo has long been thought impossible as glycine transporters (GlyT1) maintain synaptic glycine levels well below saturating concentrations. Here, we show that GINI can be triggered in vivo when mice are administered a glycine transporter-1 antagonist (GlyT1-A) prior to stroke and that this strategy provides neuroprotection. Mice pre-treated with a GlyT1-A, which elevates glycine levels, exhibited significantly smaller stroke volumes, reduced cell death, and significantly minimized behavioural deficits following stroke induction by either photothrombosis (PT) or endothelin-1 (ET-1). Moreover, we observed preservation of vasculature function and morphology in the peri-infarct area. These data strongly suggest that elevating brain glycine levels with GlyT1-As should be considered as a novel pharmacotherapy for ischemic stroke.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/42986 |
| Date | 01 December 2021 |
| Creators | Cappelli, Julia Dominique |
| Contributors | Tuana, Balwant |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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