Potent Neuroprotection After Stroke Afforded by a Double-Knot Spider-Venom Peptide That Inhibits Acid-Sensing Ion Channel 1A
Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a Irène R. Chassagnona, Claudia A. McCarthyb,c, Yanni K.-Y. China, Sandy S. Pinedaa, Angelo Keramidasd, Mehdi Moblie, Vi Phamb,c, T. Michael De Silvab,c, Joseph W. Lynchd, Robert E. Widdopb,c, Lachlan D. Rasha,f,1, and Glenn F. Kinga,1 aInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia; bBiomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; cDepartment of Pharmacology, Monash University, Clayton, VIC 3800, Australia; dQueensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia; eCentre for Advanced Imaging, The University of Queensland, St. Lucia, QLD 4072, Australia; and fSchool of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 6, 2017 (received for review September 1, 2016) Stroke is the second-leading cause of death worldwide, yet there are extracellular pH that occurs during cerebral ischemia. ASIC1a is the no drugs available to protect the brain from stroke-induced neuronal primary acid sensor in mammalian brain (9, 10) and a key mediator of injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor stroke-induced neuronal damage. Genetic ablation of ASIC1a reduces in mammalian brain and a key mediator of acidosis-induced neuronal infarct size by ∼60% after transient middle cerebral artery occlusion damage following cerebral ischemia. Genetic ablation and selective (MCAO) in mice (7), whereas pharmacologic blockade with modestly pharmacologic inhibition of ASIC1a reduces neuronal death follow- potent ASIC1a inhibitors, such as amiloride (7) and nonsteroidal anti- ing ischemic stroke in rodents.
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