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 site via an 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.

The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury

“…Given the consequences of excess Ca 2+ entering neurons and glia after injury, the authors have assessed the effects of a combination of ion channel inhibitors (ICI): Lomerizine (Lom), YM872, and Adenosine 5′-triphosphate periodate oxidized sodium salt (oxATP) to inhibit VGCCs, AMPA receptors, and P2X 7 receptors, respectively. They have shown reductions in excessive Ca 2+ influx and increased neuronal and glial cell viability in vitro using the ICI combination [ 36 ], and reduced oxidative damage, improved myelin structure, and functional recovery following administration of the combinatorial ICI following partial CNS injury in rats [ 37 , 38 , 39 ]. However, the relative inability of oxATP to cross the blood–brain barrier (BBB) and its toxicity to the cardiovascular system limits the clinical application of this compound [ 40 , 41 ].…”

Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury

“…Similarly, for clinical use, it will be necessary for future studies to determine how long after injury the combined treatment can be delayed, and efficacy maintained. In our optic nerve transection model, delayed combinatorial treatment by 6 h resulted in improvements in visual function, and the associated reduction in oxidative stress indicators (Yates et al, 2017 ). This suggests, time-delayed treatment (clinically relevant to acute SCI) of ion channel inhibitors remains a therapeutically viable option.…”