ArticleProceedings of the National Academy of Sciences of the United States of America2017
Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers, 1 of them a synthesis that pooled it.
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Who cites it
107 citing papers in PubMed, 1 synthesis or guideline pooled it, 225 citations in OpenAlex.
- Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action.Frontiers in neurology · 2020Pooled it
- Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.Pflugers Archiv : European journal of physiology · 2026Review
- The multifaceted role of ASICs channels into the nervous system and their potential use as a therapeutic target for neuro-disorders.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- The Venom Revolution in Biomedicine: Unlocking Nature's Toxin Toolkit for Therapeutic Innovation.Toxicology reports · 2026Review
- The Isolated Thumb Domain of Acid-Sensing Ion Channels Forms a Minimal Folding Unit Enabling Ligand Binding Studies.Angewandte Chemie (International ed. in English) · 2026Article
- Ancient origin and dynamic evolution of bivalent spider toxins.Molecular biology and evolution · 2026Article
- Glycaemic variability underlies myocyte dysfunction and myocardial injury risk in diabetes.Nature communications · 2026Article
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Peptides derived from exocrine secretions of venomous animals used as traditional Chinese "worm" medicines.Zoological research · 2026Review
- Ecosystem services provided by spiders.Biological reviews of the Cambridge Philosophical Society · 2025Review
- Spider venom peptides with unique fold selectively block Shaker-type potassium channels.Cellular and molecular life sciences : CMLS · 2025Article
- Review
- Review
- A dangerous liaison: Spreading depolarization and tissue acidification in cerebral ischemia.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2025Review
- Mechanism of acid-sensing ion channel modulation by Hi1a.The Journal of general physiology · 2024Article
- Enlightening the toxinological dark matter of spider venom enzymes.npj biodiversity · 2024Article
- Bioproduction Platform to Generate Functionalized Disulfide-Constrained Peptide Analogues.ACS bio & med chem Au · 2024Article
- Shining a Light on Venom-Peptide Receptors: Venom Peptides as Targeted Agents for In Vivo Molecular Imaging.Toxins · 2024Review
- Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Stroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke. Nuclear magnetic resonance structural studies reveal that Hi1a comprises two homologous inhibitor cystine knot domains separated by a short, structurally well-defined linker. In contrast with known ASIC1a inhibitors, Hi1a incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner. Whole-cell, macropatch, and single-channel electrophysiological recordings indicate that Hi1a binds to and stabilizes the closed state of the channel, thereby impeding the transition into a conducting state. Intracerebroventricular administration to rats of a single small dose of Hi1a (2 ng/kg) up to 8 h after stroke induction by occlusion of the middle cerebral artery markedly reduced infarct size, and this correlated with improved neurological and motor function, as well as with preservation of neuronal architecture. Thus, Hi1a is a powerful pharmacological tool for probing the role of ASIC1a in acid-mediated neuronal injury and various neurological disorders, and a promising lead for the development of therapeutics to protect the brain from ischemic injury.
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