Comparing modes of delivery of a combination of ion channel inhibitors for limiting secondary degeneration following partial optic nerve transection

Lillian M Toomey,Terence Mcgonigle,Melinda Fitzgerald,Maimuna Majimbi,Jennifer Rodger,Nikolas Gavriel,Gopana Gopalasingam,Carole A Bartlett

doi:10.1038/s41598-019-51886-3

Abstract

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 partial optic nerve injury protects the myelin sheath and preserves function in the ventral optic nerve, vulnerable to secondary degeneration. However, local administration is often not clinically appropriate. This study aimed to compare the efficacy of systemic and local delivery of the ion channel inhibitor combination of lomerizine, brilliant blue G (BBG) and YM872, which inhibits voltage-gated calcium channels, P2X7 receptors and Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors respectively. Following a partial optic nerve transection, adult female PVG rats were treated with BBG and YM872 delivered via osmotic mini pump directly to the injury site, or via intraperitoneal injection, both alongside oral administration of lomerizine. Myelin structure was preserved with both delivery modes of the ion channel inhibitor combination. However, there was no effect of treatment on inflammation, either peripherally or at the injury site, or on the density of oligodendroglial cells. Taken together, the data indicate that even at lower concentrations, the combinatorial treatment may be preserving myelin structure, and that systemic and local delivery are comparable at improving outcomes following neurotrauma.

Highlights

Injury to the central nervous system is exacerbated by secondary degeneration
In order to develop effective treatments for limiting secondary degeneration, therapeutics need to be trialled in appropriate animal models of injury, and partial optic nerve transection has been utilised for this purpose
Using the partial optic nerve transection model, we have previously investigated a combinatorial treatment employing the ion channel inhibitors lomerizine, Brilliant Blue G (BBG) and YM872

Summary

Introduction

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 partial optic nerve injury protects the myelin sheath and preserves function in the ventral optic nerve, vulnerable to secondary degeneration. Using the partial optic nerve transection model, we have previously investigated a combinatorial treatment employing the ion channel inhibitors lomerizine, Brilliant Blue G (BBG) and YM872 This treatment is designed to limit intracellular Ca2+ influx through voltage-gated calcium channels (VGCC)[15], P2X7 receptors[16] and Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors[17] respectively. When YM872 and BBG were locally delivered directly to the injury site via osmotic mini-pumps for 3 days following injury, alongside oral administration of lomerizine, we found that this treatment preserved function and partially protected the structure of the node of Ranvier[10]. This study aimed to compare the efficacy of local and systemic delivery of this combinatorial treatment for limiting secondary degeneration following a partial optic nerve transection, assessing inflammatory cell and oligodendroglial populations as well as structure of the node of Ranvier

Objectives

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Results

Conclusion