title: Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors.
abstract: Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca2+entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury siteviaan iPRECIO@pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca2+ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Yates
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Marcus K
authors.initials: MK
authors.lastname: Giacci
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia; Department of Experimental and Regenerative Neurosciences, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: O'Hare Doig
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia; Department of Experimental and Regenerative Neurosciences, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Wissam
authors.initials: W
authors.lastname: Chiha
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Bethany E
authors.initials: BE
authors.lastname: Ashworth
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Jade
authors.initials: J
authors.lastname: Kenna
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bartlett
authors.affiliation: Department of Experimental and Regenerative Neurosciences, School of Animal Biology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Melinda
authors.identifier: 0000-0002-4823-8179
authors.initials: M
authors.lastname: Fitzgerald
keywords: Tau phosphorylation; calcium channel inhibitor; lipid peroxidation; nerve regeneration; neural regeneration; neurotrauma; node of Ranvier; optic nerve injury; oxidative stress; secondary degeneration; seromas