Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury [version 1; referees: 1 approved, 1 approved with reservations]

Koehn, Liam M., Dong, Qing, Er, Sing-Yan, Rash, Lachlan D., King, Glenn F., Dziegielewska, Katarzyna M., Saunders, Norman R. and Habgood, Mark D. (2016) Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury [version 1; referees: 1 approved, 1 approved with reservations]. F1000Research, 5 . doi:10.12688/F1000RESEARCH.9094.1


Author Koehn, Liam M.
Dong, Qing
Er, Sing-Yan
Rash, Lachlan D.
King, Glenn F.
Dziegielewska, Katarzyna M.
Saunders, Norman R.
Habgood, Mark D.
Title Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury [version 1; referees: 1 approved, 1 approved with reservations]
Journal name F1000Research   Check publisher's open access policy
ISSN 2046-1402
Publication date 2016-07-26
Sub-type Article (original research)
DOI 10.12688/F1000RESEARCH.9094.1
Open Access Status DOI
Volume 5
Total pages 31
Place of publication London, United Kingdom
Publisher Faculty of 1000
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
 
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