Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma

Ryan O'Hare Doig, Wissam Chiha, Marcus K. Giacci, Nathanael J. Yates, Carole A. Bartlett, Nicole M. Smith, Stuart I. Hodgetts, Alan R. Harvey, Melinda Fitzgerald

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.

LanguageEnglish
Article number62
JournalBMC Neuroscience
Volume18
Issue number1
DOIs
Publication statusPublished - 14 Aug 2017

Keywords

  • Axonal degeneration
  • Ion channel inhibitor
  • Lipid peroxidation
  • Neurotrauma
  • Node of Ranvier
  • Oligodendrocyte precursor cells
  • Oxidative stress
  • Secondary degeneration
  • Traumatic injury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

O'Hare Doig, Ryan ; Chiha, Wissam ; Giacci, Marcus K. ; Yates, Nathanael J. ; Bartlett, Carole A. ; Smith, Nicole M. ; Hodgetts, Stuart I. ; Harvey, Alan R. ; Fitzgerald, Melinda. / Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma. In: BMC Neuroscience. 2017 ; Vol. 18, No. 1.
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abstract = "Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.",
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O'Hare Doig, R, Chiha, W, Giacci, MK, Yates, NJ, Bartlett, CA, Smith, NM, Hodgetts, SI, Harvey, AR & Fitzgerald, M 2017, 'Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma', BMC Neuroscience, vol. 18, no. 1, 62. https://doi.org/10.1186/s12868-017-0380-1

Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma. / O'Hare Doig, Ryan; Chiha, Wissam; Giacci, Marcus K.; Yates, Nathanael J.; Bartlett, Carole A.; Smith, Nicole M.; Hodgetts, Stuart I.; Harvey, Alan R.; Fitzgerald, Melinda.

In: BMC Neuroscience, Vol. 18, No. 1, 62, 14.08.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma

AU - O'Hare Doig, Ryan

AU - Chiha, Wissam

AU - Giacci, Marcus K.

AU - Yates, Nathanael J.

AU - Bartlett, Carole A.

AU - Smith, Nicole M.

AU - Hodgetts, Stuart I.

AU - Harvey, Alan R.

AU - Fitzgerald, Melinda

PY - 2017/8/14

Y1 - 2017/8/14

N2 - Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.

AB - Background: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. Results: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. Conclusions: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.

KW - Axonal degeneration

KW - Ion channel inhibitor

KW - Lipid peroxidation

KW - Neurotrauma

KW - Node of Ranvier

KW - Oligodendrocyte precursor cells

KW - Oxidative stress

KW - Secondary degeneration

KW - Traumatic injury

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U2 - 10.1186/s12868-017-0380-1

DO - 10.1186/s12868-017-0380-1

M3 - Article

VL - 18

JO - BMC Neuroscience

T2 - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

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