ArticleNeurobiology of disease2019
Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role of GluN2A NMDA receptors.
Article in Neurobiology of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Regulating the Impact of Hypertension on Stroke: Therapeutic Potential of a Peptide Mimetic of Tyrosine Phosphatase STEP.Journal of the American Heart Association · 2026Article
- Homocysteine enhances the excitability of cultured hippocampal neurons without altering the gene expression of voltage-gated ion channels.Molecular brain · 2025Article
- Nitric Oxide Metabolite Improves Cognitive Impairment by Reducing the Loss of Parvalbumin Inhibitory Interneurons in a Novel Mouse Model of Vascular Dementia.Current neuropharmacology · 2025Article
- Impairment of neuronal tyrosine phosphatase STEP worsens post-ischemic inflammation and brain injury under hypertensive condition.Journal of neuroinflammation · 2024Article
- Influence of the brain‑gut axis on neuroinflammation in cerebral ischemia‑reperfusion injury (Review).International journal of molecular medicine · 2024Review
- Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation.Frontiers in immunology · 2023Review
- The Role of Methyl Donors of the Methionine Cycle in Gastrointestinal Infection and Inflammation.Healthcare (Basel, Switzerland) · 2021Review
- The association between serine hydroxymethyl transferase 1 gene hypermethylation and ischemic stroke.Bosnian journal of basic medical sciences · 2021Article
- Preliminary analysis of immunoregulatory mechanism of hyperhomocysteinemia-induced brain injury in Wistar-Kyoto rats.Experimental and therapeutic medicine · 2021Article
- Hyperhomocysteinemia is an emerging comorbidity in ischemic stroke.Experimental neurology · 2021Review
- N-Methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood-retinal barrier dysfunction.Journal of molecular medicine (Berlin, Germany) · 2021Article
- N-Methyl-D-Aspartate Receptor Signaling-Protein Kinases Crosstalk in Cerebral Ischemia.Advances in experimental medicine and biology · 2021Article
- GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine.Biomolecules · 2020Article
- Review
- Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia.Biomolecules · 2020Article
- Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia.Journal of the American Heart Association · 2020Article
- Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells.International journal of medical sciences · 2020Article
- Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke.Cell death & disease · 2019Article
- Role of GluN2A NMDA receptor in homocysteine-induced prostaglandin E2 release from neurons.Journal of neurochemistry · 2019Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Hyperhomocysteinemia has been implicated in several neurodegenerative disorders including ischemic stroke. However, the pathological consequences of ischemic insult in individuals predisposed to hyperhomocysteinemia and the associated etiology are unknown. In this study, we evaluated the outcome of transient ischemic stroke in a rodent model of hyperhomocysteinemia, developed by subcutaneous implantation of osmotic pumps containing L-homocysteine into male Wistar rats. Our findings show a 42.3% mortality rate in hyperhomocysteinemic rats as compared to 7.7% in control rats. Magnetic resonance imaging of the brain in the surviving rats shows that mild hyperhomocysteinemia leads to exacerbation of ischemic injury within 24 h, which remains elevated over time. Behavioral studies further demonstrate significant deficit in sensorimotor functions in hyperhomocysteinemic rats compared to control rats. Using pharmacological inhibitors targeting the NMDAR subtypes, the study further demonstrates that inhibition of GluN2A-containing NMDARs significantly reduces ischemic brain damage in hyperhomocysteinemic rats but not in control rats, indicating that hyperhomocysteinemia-mediated exacerbation of ischemic brain injury involves GluN2A-NMDAR signaling. Complementary studies in GluN2A-knockout mice show that in the absence of GluN2A-NMDARs, hyperhomocysteinemia-associated exacerbation of ischemic brain injury is blocked, confirming that GluN2A-NMDAR activation is a critical determinant of the severity of ischemic damage under hyperhomocysteinemic conditions. Furthermore, at the molecular level we observe GluN2A-NMDAR dependent sustained increase in ERK MAPK phosphorylation under hyperhomocysteinemic condition that has been shown to be involved in homocysteine-induced neurotoxicity. Taken together, the findings show that hyperhomocysteinemia triggers a unique signaling pathway that in conjunction with ischemia-induced pathways enhance the pathology of stroke under hyperhomocysteinemic conditions.
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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.