Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury
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...
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| Format: | Journal Article |
| Language: | English |
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FRONTIERS MEDIA SA
2020
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1061791 http://hdl.handle.net/20.500.11937/81492 |
| _version_ | 1848764377054838784 |
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| author | O’Hare Doig, R.L. Santhakumar, S. Fehily, B. Raja, S. Solomon, T. Bartlett, C.A. Fitzgerald, Melinda Hodgetts, S.I. |
| author_facet | O’Hare Doig, R.L. Santhakumar, S. Fehily, B. Raja, S. Solomon, T. Bartlett, C.A. Fitzgerald, Melinda Hodgetts, S.I. |
| author_sort | O’Hare Doig, R.L. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T11:18:23Z |
| format | Journal Article |
| id | curtin-20.500.11937-81492 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:18:23Z |
| publishDate | 2020 |
| publisher | FRONTIERS MEDIA SA |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-814922020-11-04T01:43:08Z Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury O’Hare Doig, R.L. Santhakumar, S. Fehily, B. Raja, S. Solomon, T. Bartlett, C.A. Fitzgerald, Melinda Hodgetts, S.I. Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology spinal cord injury secondary degeneration ion channel inhibitors glia calcium (Ca2+) oxidative stress CHRONIC SECONDARY DEGENERATION OPTIC-NERVE TRANSECTION BETA-III TUBULIN BRILLIANT-BLUE-G OXIDATIVE STRESS SELECTIVE VULNERABILITY LIPID-PEROXIDATION TIME-COURSE CALCIUM-CHANNELS MOTOR-NEURONS 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. 2020 Journal Article http://hdl.handle.net/20.500.11937/81492 10.3389/fnmol.2020.00085 English http://purl.org/au-research/grants/nhmrc/1061791 http://creativecommons.org/licenses/by/4.0/ FRONTIERS MEDIA SA fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology spinal cord injury secondary degeneration ion channel inhibitors glia calcium (Ca2+) oxidative stress CHRONIC SECONDARY DEGENERATION OPTIC-NERVE TRANSECTION BETA-III TUBULIN BRILLIANT-BLUE-G OXIDATIVE STRESS SELECTIVE VULNERABILITY LIPID-PEROXIDATION TIME-COURSE CALCIUM-CHANNELS MOTOR-NEURONS O’Hare Doig, R.L. Santhakumar, S. Fehily, B. Raja, S. Solomon, T. Bartlett, C.A. Fitzgerald, Melinda Hodgetts, S.I. Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title | Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title_full | Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title_fullStr | Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title_full_unstemmed | Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title_short | Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury |
| title_sort | acute cellular and functional changes with a combinatorial treatment of ion channel inhibitors following spinal cord injury |
| topic | Science & Technology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology spinal cord injury secondary degeneration ion channel inhibitors glia calcium (Ca2+) oxidative stress CHRONIC SECONDARY DEGENERATION OPTIC-NERVE TRANSECTION BETA-III TUBULIN BRILLIANT-BLUE-G OXIDATIVE STRESS SELECTIVE VULNERABILITY LIPID-PEROXIDATION TIME-COURSE CALCIUM-CHANNELS MOTOR-NEURONS |
| url | http://purl.org/au-research/grants/nhmrc/1061791 http://hdl.handle.net/20.500.11937/81492 |