ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2006
Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 1 of them a synthesis that pooled it.
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Who cites it
114 citing papers in PubMed, 1 synthesis or guideline pooled it, 235 citations in OpenAlex.
- Anesthetic management of unruptured intracranial aneurysms: a qualitative systematic review.Neurosurgical review · 2021Pooled it
- Ischemic stroke neuroprotection revisited: translational barriers and a phase-resolved, biomarker-anchored framework.Archives of pharmacal research · 2026Review
- Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.Communications biology · 2025Article
- Bridging Inflammation and Repair: The Promise of MFG-E8 in Ischemic Stroke Therapy.International journal of molecular sciences · 2025Review
- A genetically encoded secreted toxin potentiates synaptic NMDA receptors in hippocampal neurons and confers neuroprotection.PNAS nexus · 2025Article
- NMDAR inhibitor preconditioned mesenchymal stromal cell-derived extracellular vesicles enhance post-stroke recovery by targeting excitotoxicity and neuronal regeneration.Frontiers in cellular neuroscience · 2025Article
- Neuronal activity drives PCDH9 cleavage and nuclear translocation to coordinate structural and functional remodeling.Frontiers in cellular neuroscience · 2025Article
- GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer's Disease Animal Model.Neurochemical research · 2024Article
- Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.Antioxidants (Basel, Switzerland) · 2023Article
- Different Effects and Mechanisms of Selenium Compounds in Improving Pathology in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2023Article
- Synaptic Activity Regulates Mitochondrial Iron Metabolism to Enhance Neuronal Bioenergetics.International journal of molecular sciences · 2023Article
- Memantine has a nicotinic neuroprotective pathway in acute hippocampal slices after an NMDA insult.Toxicology in vitro : an international journal published in association with BIBRA · 2022Article
- Magnesium Oxide/Poly(l-lactide-co-ε-caprolactone) Scaffolds Loaded with Neural Morphogens Promote Spinal Cord Repair through Targeting the Calcium Influx and Neuronal Differentiation of Neural Stem Cells.Advanced healthcare materials · 2022Article
- Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2022Review
- Polygalasaponin F protects hippocampal neurons against glutamate-induced cytotoxicity.Neural regeneration research · 2022Article
- Stress-Related Dysfunction of Adult Hippocampal Neurogenesis-An Attempt for Understanding Resilience?International journal of molecular sciences · 2021Review
- Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2-p53 Pathway.International journal of molecular sciences · 2021Article
- A Rationale for Hypoxic and Chemical Conditioning in Huntington's Disease.International journal of molecular sciences · 2021Review
- Refocusing the Brain: New Approaches in Neuroprotection Against Ischemic Injury.Neurochemical research · 2021Review
- Comparison of three administration modes for establishing a zebrafish seizure model induced by N-Methyl-D-aspartic acid.World journal of psychiatry · 2020Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing. Both acute and long-lasting phases of neuroprotection in the face of apoptotic or excitotoxic insults are dependent on this firing enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box subgroup O (FOXO) export and glycogen synthase kinase 3beta (GSK3beta) inhibition and cAMP response element-binding protein-dependent (CREB-dependent) activation of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of NMDA via this action potential-dependent route. In contrast, NMDA doses on the other side of the toxicity threshold do not favor synaptic NMDA receptor activation because they strongly suppress firing rates below baseline. The classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: via increased firing the synaptic signaling dominates at low doses, whereas firing becomes suppressed and extrasynaptic signaling dominates as the toxicity threshold is crossed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.