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Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke.

ABSTRACT: Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive N-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI) in vitro. Here, we report that following an ischemic event, in vivo, GINI also occurs and provides neuroprotection in the presence of a GlyT1 antagonist (GlyT1-A). Mice pretreated with a GlyT1-A, which increases synaptic glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioral deficits following stroke induction by either photothrombosis or endothelin-1. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, GlyT1 could be a new target for the treatment of ischemic stroke.

SUBMITTER: Cappelli J

PROVIDER: S-EPMC8689229 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke.

Cappelli Julia J Khacho Pamela P Wang Boyang B Sokolovski Alexandra A Bakkar Wafae W Raymond Sophie S Ahlskog Nina N Pitney Julian J Wu Junzheng J Chudalayandi Prakash P Wong Adrian Y C AYC Bergeron Richard R

iScience 20211203 1

Ischemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitive <i>N</i>-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI) <i>in vitr ...[more]

PMID: 34977503

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Project description:Background and purpose: A major gap in the field of ischemic preconditioning (IPC) is whether or not long-lasting neuroprotection can be achieved. Moreover, the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain. To fill these gaps, we tested the hypothesis that IPC exerts long-lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses, nuclear factor erythroid 2-related factor 2 (Nrf2). We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood-brain barrier-permeable Nrf2 activator, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-trifluoethyl amide (CDDO-TFEA).Methods: IPC was induced by transient middle cerebral artery occlusion (MCAO) for 12 min, and ischemic stroke was generated by MCAO for 60 min in wild-type (WT) or Nrf2 knockout (KO) mice. Sensorimotor function, learning/memory skills, and brain tissue loss were measured up to 35 days after stroke. Primary rodent cortical neurons from wildtype (WT) and Nrf2 KO mice were subjected to lethal oxygen-glucose deprivation (OGD) or a brief OGD episode as a preconditioning (PC) stimulus before OGD. Cell viability/death, lipid electrophile generation, and Nrf2 activation were measured. CDDO-TFEA or its vehicle was administered in vivo for three consecutive days before MCAO. Tissue loss and neurological tests were performed 35 days after stroke.Results: IPC significantly reduced sensorimotor deficits, post-stroke cognitive impairments, and brain tissue loss, 35 days after MCAO in WT mice. These enduring protective effects of IPC were inhibited in Nrf2 KO mice. In neuronal cultures, PC also endowed primary neurons with ischemic tolerance against OGD-induced cell death, an effect that was abolished by loss of Nrf2 expression in KO neurons. PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway. The mechanism underlying IPC may be translatable, as exogenous administration of the Nrf2 activator CDDO-TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO.Conclusions: IPC provides long-lasting neuroprotection against ischemic brain injury and post-stroke cognitive dysfunction. Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury.

Dataset Information

Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke.

Publications

Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke.

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