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

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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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The authors declare that they have no conflict of interest.

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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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  • DOI: https://doi.org/10.1007/s00221-018-5414-0

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