POS-FRI-051

Potent neuroprotection after stroke afforded by a double-knot spider toxin that inhibits acid-sensing ion channel 1a

IR Chassagnon1, CA McCarthy2, YKY Chin1, SS Pineda1, A Keramidas3, M Mobli4, JW Lynch3, RE Widdop2, LD Rash1,5 and GF King1

  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia
  2. Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia
  3. Queensland Brain Institute, The University of Queensland, St Lucia, QLD 4072, Australia
  4. Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia
  5. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia

Acid-sensing ion channels (ASICs) are pH-dependent cation channels that are widely expressed throughout the nervous system. ASIC1a is the dominant ASIC subtype in mammalian brain and it is a key contributor to the neurodegeneration observed following ischaemic stroke. We discovered a novel spider-venom peptide (Hi1a) that blocks ASIC1a with subnanomolar potency and is 30-fold more selective for ASIC1a over other ASIC subtypes. Determination of the structure of Hi1a using NMR revealed that is a double knot toxin comprised of two inhibitor cystine knot motifs joined by short linker. Hi1a has a unique mode of action that differs from previously characterised ASIC1a modulators. Inhibition of ASIC1a by Hi1a is not complete as ~30% of channel current remains after exposure to saturating concentrations of peptide. Moreover, the inhibition of ASIC1a pH-induced currents is irreversible. We evaluated whether Hi1a is neuroprotective in a rat model of transient focal ischaemia. A single low dose of Hi1a (2 ng/kg, administered to the cerebroventricular) up to 8 hours post-stroke markedly reduced infarct size and neurological deficits without adverse effects on motor activity. Thus, Hi1a represents an exciting lead molecule for development of therapeutics for neurodegeneration and other pathophysiological conditions involving ASIC1a.