Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma.
Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca2+ 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 Ca2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X7 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 Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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.
['Savigni|Donna L|DL|', "O'Hare Doig|Ryan L|RL|", 'Szymanski|Charis R|CR|', 'Bartlett|Carole A|CA|', 'Lozić|Ivan|I|', 'Smith|Nicole M|NM|', 'Fitzgerald|Melinda|M|']
D000255:Adenosine Triphosphate D000818:Animals D051792:Basic Helix-Loop-Helix Transcription Factors D002121:Calcium Channel Blockers D015816:Cell Adhesion Molecules, Neuronal D004195:Disease Models, Animal D004338:Drug Combinations D005260:Female D009682:Magnetic Resonance Spectroscopy D009410:Nerve Degeneration D009419:Nerve Tissue Proteins D017120:Nystagmus, Optokinetic D009900:Optic Nerve D020221:Optic Nerve Injuries D010211:Papilledema D010879:Piperazines D011901:Ranvier's Nodes D051381:Rats D012165:Retinal Ganglion Cells D044005:Tetrahydroisoquinolines D014316:Tritium
Secondary degeneration Neurotrauma Myelin optic nerve lomerizine oxidised adenosine-triphosphate oxATP 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid INQ α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA retinal ganglion cell ON Node/paranode complex ATP Ca(2+) channel inhibitors Lom Myelin compaction N-methyl-d-aspartic acid NMDA OCT OPCs Oxidative stress PBS PFA PT RGC SEM TEM VGCCs Visual system adenosine triphosphate i.p. intraperitoneally oligodendrocyte precursor cells optical cutting temperature paraformaldehyde partial transection phosphate buffered saline standard error of the mean transmission electron microscopy voltage-gated calcium channels