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

Yilin Mao, Anna M. B. Black, Hannah R. Milbourn, Samra Krakonja, Michael Nesbit, Carole A. Bartlett, Brooke Fehily, Ryu Takechi, Nathanael J. Yates, Melinda Fitzgerald

Research output: Contribution to journalArticle

Abstract

Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X₇ receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p <0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p <0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p <0.01). The authors' findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI.
Original languageEnglish
Article number3408
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume19
Issue number11
DOIs
Publication statusPublished - Nov 2018
Externally publishedYes

Fingerprint

Brain Concussion
brain damage
Ion Channels
Ranvier's Nodes
inhibitors
rats
Rats
Brain
inorganic peroxides
Manganese
Superoxide Dismutase
manganese
Ions
vehicles
homeostasis
central nervous system
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
Wounds and Injuries
abnormalities

Cite this

Mao, Yilin ; Black, Anna M. B. ; Milbourn, Hannah R. ; Krakonja, Samra ; Nesbit, Michael ; Bartlett, Carole A. ; Fehily, Brooke ; Takechi, Ryu ; Yates, Nathanael J. ; Fitzgerald, Melinda. / The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury. In: International Journal of Molecular Sciences. 2018 ; Vol. 19, No. 11.
@article{2492584392674782a9d3aa60c6abadfb,
title = "The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury",
abstract = "Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X₇ receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p <0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p <0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p <0.01). The authors' findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI.",
keywords = "neurotrauma, repeated mild traumatic brain injury, ion channel inhibitors, oxidative stress, node of Ranvier, BRILLIANT-BLUE-G, AMPA RECEPTOR ANTAGONIST, OPTIC-NERVE TRANSECTION, GANGLION-CELL DEATH, CLOSED-HEAD INJURY, OXIDATIVE STRESS, SECONDARY DEGENERATION, MOUSE MODEL, SUPEROXIDE-DISMUTASE",
author = "Yilin Mao and Black, {Anna M. B.} and Milbourn, {Hannah R.} and Samra Krakonja and Michael Nesbit and Bartlett, {Carole A.} and Brooke Fehily and Ryu Takechi and Yates, {Nathanael J.} and Melinda Fitzgerald",
year = "2018",
month = "11",
doi = "10.3390/ijms19113408",
language = "English",
volume = "19",
journal = "Internation Journal of Molecular Sciences",
issn = "1422-0067",
publisher = "MDPI AG",
number = "11",

}

The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury. / Mao, Yilin; Black, Anna M. B.; Milbourn, Hannah R.; Krakonja, Samra; Nesbit, Michael; Bartlett, Carole A.; Fehily, Brooke; Takechi, Ryu; Yates, Nathanael J.; Fitzgerald, Melinda.

In: International Journal of Molecular Sciences, Vol. 19, No. 11, 3408, 11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury

AU - Mao, Yilin

AU - Black, Anna M. B.

AU - Milbourn, Hannah R.

AU - Krakonja, Samra

AU - Nesbit, Michael

AU - Bartlett, Carole A.

AU - Fehily, Brooke

AU - Takechi, Ryu

AU - Yates, Nathanael J.

AU - Fitzgerald, Melinda

PY - 2018/11

Y1 - 2018/11

N2 - Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X₇ receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p <0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p <0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p <0.01). The authors' findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI.

AB - Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X₇ receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p <0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p <0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p <0.01). The authors' findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI.

KW - neurotrauma

KW - repeated mild traumatic brain injury

KW - ion channel inhibitors

KW - oxidative stress

KW - node of Ranvier

KW - BRILLIANT-BLUE-G

KW - AMPA RECEPTOR ANTAGONIST

KW - OPTIC-NERVE TRANSECTION

KW - GANGLION-CELL DEATH

KW - CLOSED-HEAD INJURY

KW - OXIDATIVE STRESS

KW - SECONDARY DEGENERATION

KW - MOUSE MODEL

KW - SUPEROXIDE-DISMUTASE

UR - http://www.scopus.com/inward/record.url?scp=85055912761&partnerID=8YFLogxK

U2 - 10.3390/ijms19113408

DO - 10.3390/ijms19113408

M3 - Article

VL - 19

JO - Internation Journal of Molecular Sciences

JF - Internation Journal of Molecular Sciences

SN - 1422-0067

IS - 11

M1 - 3408

ER -