title: PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a.
abstract: Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and plays a major role in neuronal injury following cerebral ischemia. Evidence that inhibition of ASIC1a might be neuroprotective following stroke was previously obtained using "PcTx1 venom" from the tarantula Psalmopeous cambridgei. We show here that the ASIC1a-selective blocker PcTx1 is present at only 0.4% abundance in this venom, leading to uncertainty as to whether the observed neuroprotective effects were due to PcTx1 blockade of ASIC1a or inhibition of other ion channels and receptors by the hundreds of peptides and small molecules present in the venom. We therefore examined whether pure PcTx1 is neuroprotective in a conscious model of stroke via direct inhibition of ASIC1a. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats (SHR) by administering endothelin-1 to the middle cerebral artery via a surgically implanted cannula. Two hours later, SHR were treated with a single intracerebroventricular (i.c.v.) dose of PcTx1 (1 ng/kg), an ASIC1a-inactive mutant of PcTx1 (1 ng/kg), or saline, and ledged beam and neurological tests were used to assess the severity of symptomatic changes. PcTx1 markedly reduced cortical and striatal infarct volumes measured 72 h post-stroke, which correlated with improvements in neurological score, motor function and preservation of neuronal architecture. In contrast, the inactive PcTx1 analogue had no effect on stroke outcome. This is the first demonstration that selective pharmacological inhibition of ASIC1a is neuroprotective in conscious SHRs, thus validating inhibition of ASIC1a as a potential treatment for stroke.
authors: Department of Pharmacology, Monash University, Clayton, Vic 3800, Australia.
authors: Claudia A
authors: CA
authors: McCarthy
authors: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors: Lachlan D
authors: LD
authors: Rash
authors: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors: Irène R
authors: IR
authors: Chassagnon
authors: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: glenn.king@uq.edu.au.
authors: Glenn F
authors: GF
authors: King
authors: Department of Pharmacology, Monash University, Clayton, Vic 3800, Australia. Electronic address: robert.widdop@monash.edu.
authors: Robert E
authors: RE
authors: Widdop
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D011918:Rats, Inbred SHR; D012720:Severity of Illness Index; D013111:Spider Venoms / Q000235:genetics / Q000494:pharmacology*; D013112:Spiders; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D019332:Endothelin-1; D018696:Neuroprotective Agents; C413209:PcTX1 protein, Psalmopoeus cambridgei; D010455:Peptides; D013111:Spider Venoms
keywords: Acid-sensing ion channel 1a; Acidosis; Infarction; PcTx1; Spontaneously hypertensive rats; Stroke