Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma
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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 Ca 2+ 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 Ca 2+ channel inhibitor Lomerizine (Lom), the Ca 2+ 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.
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Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotraumaSavigni, D.; O'Hare Doig, R.; Szymanski, C.; Bartlett, C.; Lozic, I.; Smith, N.; Fitzgerald, Melinda (2013)Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca 2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca ...
Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitorsYates, N.; Giacci, M.; O'Hare Doig, R.; Chiha, W.; Ashworth, B.; Kenna, J.; Bartlett, C.; Fitzgerald, Melinda (2017)Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine ...
Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitorsYates, N.; Giacci, M.; O Hare Doig, R.; Chiha, W.; Ashworth, B.; Kenna, J.; Bartlett, C.; Fitzgerald, Melinda (2017)© 2017, Medknow Publications. All rights reserved. Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. ...