Abstract
| Original language | English |
|---|---|
| Article number | 3408 |
| Number of pages | 18 |
| Journal | International Journal of Molecular Sciences |
| Volume | 19 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2018 |
| Externally published | Yes |
Fingerprint
Cite this
}
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 journal › Article
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 -