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

Ryan L. 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

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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 P2X(7) 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.

Original languageEnglish
Article number62
Number of pages16
JournalBMC Neuroscience
Volume18
DOIs
Publication statusPublished - 14 Aug 2017

Cite this

@article{a812db803bd646609241c4c843be8dae,
title = "Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma",
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 P2X(7) 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.",
keywords = "Secondary degeneration, Neurotrauma, Traumatic injury, Ion channel inhibitor, Axonal degeneration, Node of Ranvier, Lipid peroxidation, Oligodendrocyte precursor cells, Oxidative stress, SPINAL-CORD-INJURY, TRAUMATIC BRAIN-INJURY, ACID RECEPTOR ANTAGONIST, PEROXIDATION BY-PRODUCT, OPTIC-NERVE TRANSECTION, NOGO-A EXPRESSION, OXIDATIVE STRESS, WHITE-MATTER, LIPID-PEROXIDATION, ALZHEIMERS-DISEASE",
author = "Doig, {Ryan L. O'Hare} and Wissam Chiha and Giacci, {Marcus K.} and Yates, {Nathanael J.} and Bartlett, {Carole A.} and Smith, {Nicole M.} and Hodgetts, {Stuart I.} and Harvey, {Alan R.} and Melinda Fitzgerald",
year = "2017",
month = "8",
day = "14",
doi = "10.1186/s12868-017-0380-1",
language = "English",
volume = "18",
journal = "BMC Neuroscience",
issn = "1471-2202",
publisher = "BioMed Central",

}

Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma. / Doig, Ryan L. O'Hare; 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, 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 - Doig, Ryan L. O'Hare

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 P2X(7) 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 P2X(7) 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 - Secondary degeneration

KW - Neurotrauma

KW - Traumatic injury

KW - Ion channel inhibitor

KW - Axonal degeneration

KW - Node of Ranvier

KW - Lipid peroxidation

KW - Oligodendrocyte precursor cells

KW - Oxidative stress

KW - SPINAL-CORD-INJURY

KW - TRAUMATIC BRAIN-INJURY

KW - ACID RECEPTOR ANTAGONIST

KW - PEROXIDATION BY-PRODUCT

KW - OPTIC-NERVE TRANSECTION

KW - NOGO-A EXPRESSION

KW - OXIDATIVE STRESS

KW - WHITE-MATTER

KW - LIPID-PEROXIDATION

KW - ALZHEIMERS-DISEASE

U2 - 10.1186/s12868-017-0380-1

DO - 10.1186/s12868-017-0380-1

M3 - Article

VL - 18

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

M1 - 62

ER -