title: Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury.
abstract: Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a "treatment window" through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Liam M
authors.initials: LM
authors.lastname: Koehn
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Natassya M
authors.initials: NM
authors.lastname: Noor
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.
authors.forename: Sing-Yan
authors.initials: SY
authors.lastname: Er
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia; School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia.
authors.forename: Lachlan D
authors.initials: LD
authors.lastname: Rash
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Dziegielewska
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Norman R
authors.initials: NR
authors.lastname: Saunders
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Habgood
keywords: Acid-sensing ion channel; Blood-spinal cord barrier; Ischaemia; Neuroprotection; PcTx1; Psalmotoxin; Spinal trauma; Transcriptomic