Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma
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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 2+ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca 2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca 2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X 7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4- tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca 2+ permeable a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca 2+ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca 2+ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca 2+ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca 2+ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.
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Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotraumaO'Hare Doig, R.; Chiha, W.; Giacci, M.; Yates, N.; Bartlett, C.; Smith, N.; Hodgetts, S.; Harvey, A.; Fitzgerald, Melinda (2017)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 ...
Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord InjuryO’Hare Doig, R.L.; Santhakumar, S.; Fehily, B.; Raja, S.; Solomon, T.; Bartlett, C.A.; Fitzgerald, Melinda ; Hodgetts, S.I. (2020)Reducing the extent of secondary degeneration following spinal cord injury (SCI) is necessary to preserve function, but treatment options have thus far been limited. A combination of the ion channel inhibitors Lomerizine ...
Comparing modes of delivery of a combination of ion channel inhibitors for limiting secondary degeneration following partial optic nerve transectionToomey, Lilian; Bartlett, C.A.; Gavriel, N.; McGonigle, Terence; Majimbi, Maimuna; Gopalasingam, G.; Rodger, J.; Fitzgerald, Melinda (2019)© 2019, The Author(s). Injury to the central nervous system is exacerbated by secondary degeneration. Previous research has shown that a combination of orally and locally administered ion channel inhibitors following ...