title: Three Ca2+ channel inhibitors in combination limit chronic secondary degeneration following neurotrauma.
abstract: 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.
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Donna L
authors: DL
authors: Savigni
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Ryan L
authors: RL
authors: O'Hare Doig
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Charis R
authors: CR
authors: Szymanski
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Carole A
authors: CA
authors: Bartlett
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Ivan
authors: I
authors: Lozić
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Nicole M
authors: NM
authors: Smith
authors: Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia. Electronic address: lindy.fitzgerald@uwa.edu.au.
authors: Melinda
authors: M
authors: Fitzgerald
mesh_terms: D000255:Adenosine Triphosphate / Q000627:therapeutic use; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017120:Nystagmus, Optokinetic / Q000187:drug effects; D009900:Optic Nerve / Q000473:pathology / Q000648:ultrastructure; D020221:Optic Nerve Injuries / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D010211:Papilledema / Q000209:etiology / Q000517:prevention & control; D010879:Piperazines / Q000627:therapeutic use; D011901:Ranvier's Nodes / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014316:Tritium
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D002121:Calcium Channel Blockers; D015816:Cell Adhesion Molecules, Neuronal; D004338:Drug Combinations; D009419:Nerve Tissue Proteins; D010879:Piperazines; D044005:Tetrahydroisoquinolines; D014316:Tritium; C105177:Cntnap1 protein, rat; C498633:Olig1 protein, rat; C052424:lomerizine
keywords: 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid; AMPA; ATP; Ca(2+) channel inhibitors; INQ; Lom; Myelin; Myelin compaction; N-methyl-d-aspartic acid; NMDA; Neurotrauma; Node/paranode complex; OCT; ON; OPCs; Oxidative stress; PBS; PFA; PT; RGC; SEM; Secondary degeneration; TEM; VGCCs; Visual system; adenosine triphosphate; i.p.; intraperitoneally; lomerizine; oligodendrocyte precursor cells; optic nerve; optical cutting temperature; oxATP; oxidised adenosine-triphosphate; paraformaldehyde; partial transection; phosphate buffered saline; retinal ganglion cell; standard error of the mean; transmission electron microscopy; voltage-gated calcium channels; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid