PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a

McCarthy, Claudia A., Rash, Lachlan D., Chassagnon, Irene R., King, Glenn F. and Widdop, Robert E. (2015) PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a. Neuropharmacology, 99 650-657. doi:10.1016/j.neuropharm.2015.08.040


Author McCarthy, Claudia A.
Rash, Lachlan D.
Chassagnon, Irene R.
King, Glenn F.
Widdop, Robert E.
Title PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 0028-3908
1873-7064
Publication date 2015-12-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2015.08.040
Volume 99
Start page 650
End page 657
Total pages 8
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon Press
Collection year 2016
Language eng
Formatted 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.
Keyword Acid-sensing ion channel 1a
Acidosis
Infarction
PcTx1
Spontaneously hypertensive rats
Stroke
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 18 Sep 2015, 12:27:10 EST by Susan Allen on behalf of Institute for Molecular Bioscience