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Comparison of ion channel inhibitor combinations for limiting secondary degeneration following partial optic nerve transection

Abstract

Following neurotrauma, secondary degeneration of neurons and glia adjacent to the injury leads to further functional loss. A combination of ion channel inhibitors (lomerizine + oxATP + YM872) has been shown to be effective at limiting structural and functional loss due to secondary degeneration. Here we assess efficacy of the combination where oxATP is replaced with Brilliant Blue G (BBG), a more clinically applicable P2X7 receptor inhibitor. Partial optic nerve transection was used to model secondary degeneration in adult female rats. Animals were treated with combinations of lomerizine + YM872 + oxATP or lomerizine + YM872 + BBG, delivered via osmotic mini-pump directly to the injury site. Outcomes assessed were Iba1 + and ED1 + microglia and macrophages, oligodendroglial cell numbers, node/paranode structure and visual function using the optokinetic nystagmus test. The lomerizine + BBG + YM872 combination was at least as effective at the tested concentrations as the lomerizine + oxATP + YM872 combination at preserving node/paranode structure and visual function when delivered locally. However, neither ion channel inhibitor combination significantly improved microglial/macrophage nor oligodendroglial numbers compared to vehicle-treated controls. In conclusion, a locally delivered combination of ion channel inhibitors incorporating lomerizine + BBG + YM872 is at least as effective at limiting secondary degeneration following partial injury to the optic nerve as the combination incorporating oxATP.

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Acknowledgements

MF is supported by an NHMRC Career Development Fellowship (APP1087114).

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Correspondence to Melinda Fitzgerald.

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Toomey, L.M., Bartlett, C.A., Majimbi, M. et al. Comparison of ion channel inhibitor combinations for limiting secondary degeneration following partial optic nerve transection. Exp Brain Res 237, 161–171 (2019). https://doi.org/10.1007/s00221-018-5414-0

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Keywords

  • Secondary degeneration
  • Neurotrauma
  • Ion channel inhibitor
  • Myelin
  • Visual function