Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors

Nathanael J. Yates, Marcus K. Giacci, R.L. O'Hare Doig, Wissam Chiha, Bethany E. Ashworth, Jade Kenna, Carole A. Bartlett, Melinda Fitzgerald

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)307-316
Number of pages10
JournalNeural Regeneration Research
Volume12
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017

Fingerprint

Optic Nerve Injuries
Ion Channels
Seroma
Purinergic P2X7 Receptors
Ranvier's Nodes
Nervous System Trauma
Purinergic P2 Receptors
AMPA Receptors
Wounds and Injuries
Calcium Channel Blockers
Neuroprotective Agents
Oxidative Stress
Central Nervous System
Therapeutics
Infection

Cite this

Yates, Nathanael J. ; Giacci, Marcus K. ; O'Hare Doig, R.L. ; Chiha, Wissam ; Ashworth, Bethany E. ; Kenna, Jade ; Bartlett, Carole A. ; Fitzgerald, Melinda. / Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors. In: Neural Regeneration Research. 2017 ; Vol. 12, No. 2. pp. 307-316.
@article{1b793c411a1548f78e9996e9eb204bd3,
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 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.",
keywords = "Calcium channel inhibitor, Lipid peroxidation, Nerve regeneration, Neural regeneration, Neurotrauma, Node of Ranvier, Optic nerve injury, Oxidative stress, Secondary degeneration, Seromas, Tau phosphorylation",
author = "Yates, {Nathanael J.} and Giacci, {Marcus K.} and {O'Hare Doig}, R.L. and Wissam Chiha and Ashworth, {Bethany E.} and Jade Kenna and Bartlett, {Carole A.} and Melinda Fitzgerald",
year = "2017",
month = "2",
day = "1",
doi = "10.4103/1673-5374.200814",
language = "English",
volume = "12",
pages = "307--316",
journal = "Neural Regeneration Research",
issn = "1673-5374",
publisher = "Wolters Kluwer Medknow Publications",
number = "2",

}

Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors. / Yates, Nathanael J.; Giacci, Marcus K.; O'Hare Doig, R.L.; Chiha, Wissam; Ashworth, Bethany E.; Kenna, Jade; Bartlett, Carole A.; Fitzgerald, Melinda.

In: Neural Regeneration Research, Vol. 12, No. 2, 01.02.2017, p. 307-316.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Delayed treatment of secondary degeneration following acute optic nerve transection using a combination of ion channel inhibitors

AU - Yates, Nathanael J.

AU - Giacci, Marcus K.

AU - O'Hare Doig, R.L.

AU - Chiha, Wissam

AU - Ashworth, Bethany E.

AU - Kenna, Jade

AU - Bartlett, Carole A.

AU - Fitzgerald, Melinda

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

KW - Calcium channel inhibitor

KW - Lipid peroxidation

KW - Nerve regeneration

KW - Neural regeneration

KW - Neurotrauma

KW - Node of Ranvier

KW - Optic nerve injury

KW - Oxidative stress

KW - Secondary degeneration

KW - Seromas

KW - Tau phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=85014952635&partnerID=8YFLogxK

U2 - 10.4103/1673-5374.200814

DO - 10.4103/1673-5374.200814

M3 - Article

VL - 12

SP - 307

EP - 316

JO - Neural Regeneration Research

JF - Neural Regeneration Research

SN - 1673-5374

IS - 2

ER -