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https://hdl.handle.net/2440/130183
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Type: | Journal article |
Title: | Acute cellular and functional changes with a combinatorial treatment of ion channel inhibitors following spinal cord injury |
Author: | O Hare Doig, R.L. Santhakumar, S. Fehily, B. Raja, S. Solomon, T. Bartlett, C.A. Fitzgerald, M. Hodgetts, S.I. |
Citation: | Frontiers in Molecular Neuroscience, 2020; 13:85-85 |
Publisher: | Frontiers |
Issue Date: | 2020 |
ISSN: | 1662-5099 1662-5099 |
Statement of Responsibility: | Ryan L. O, Hare Doig, Sreya Santhakumar, Brooke Fehily, Sushmitha Raja, Tanya Solomon ... et al. |
Abstract: | Reducing the extent of secondary degeneration following spinal cord injury (SCI) is necessary to preserve function, but treatment options have thus far been limited. A combination of the ion channel inhibitors Lomerizine (Lom), YM872 and oxATP, to inhibit voltage-gated Ca2+ channels, Ca2+ permeable AMPA receptors, and purinergic P2X7 receptors respectively, effectively limits secondary consequences of injury in in vitro and in vivo models of CNS injury. Here, we investigated the efficacy of these inhibitors in a clinically relevant model of SCI. Fischer (F344) rats were subjected to a moderate (150 kD) contusive SCI at thoracic level T10 and assessed at 2 weeks or 10 weeks post-injury. Lom was delivered orally twice daily and YM872 and oxATP were delivered via osmotic mini-pump implanted at the time of SCI until 2 weeks following injury. Open field locomotion analysis revealed that treatment with the three inhibitors in combination improved the rate of functional recovery of the hind limb (compared to controls) as early as 1-day post-injury, with beneficial effects persisting to 14 days post-injury, while all three inhibitors were present. At 2 weeks following combinatorial treatment, the functional improvement was associated with significantly decreased cyst size, increased immunoreactivity of β-III tubulin+ve axons, myelin basic protein, and reduced lipid peroxidation by-products, and increased CC1+ve oligodendrocytes and NG2+ve/PDGFα+ve oligodendrocyte progenitor cell densities, compared to vehicle-treated SCI animals. The combination of Lom, oxATP, and YM872 shows preclinical promise for control of secondary degeneration following SCI, and further investigation of long-term sustained treatment is warranted. |
Keywords: | calcium (Ca2+) glia ion channel inhibitors oxidative stress secondary degeneration spinal cord injury |
Rights: | © 2020 O’Hare Doig, Santhakumar, Fehily, Raja, Solomon, Bartlett, Fitzgerald and Hodgetts. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
DOI: | 10.3389/fnmol.2020.00085 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1061791 |
Published version: | http://dx.doi.org/10.3389/fnmol.2020.00085 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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