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.

Macrophage and adipocyte interaction as a source of inflammation in kidney disease

“…In our current study, we present data supporting the concept that uremia stimulates adipocyte production of inflammatory cytokines and promotes lipolysis. This finding is consistent with prior studies that reported increased IL-6 and TNF-α expression in 3T3-L1 adipocytes exposed to uremic toxins such as indoxyl sulfate and p-cresyl sulfate 28 , 29 . Furthermore, we have also demonstrated that macrophages exposed to uremia drive adipocytes to produce inflammatory cytokines.…”

Post-traumatic headache due to mild traumatic brain injury: Current knowledge and future directions

“…In support of this mechanism, animal studies have demonstrated a loss of diffuse noxious inhibitory controls (DNIC) after mTBI, while human studies have demonstrated a loss of conditioned pain modulation, findings reflective of a reduction in pain inhibition (30)(31)(32). As reviewed more comprehensively in an article by H Ashina and colleagues, cellular injury due to mTBI results in loss of normal ionic homeostasis, energy depletion, oxidative stress, and axonal damage, processes that could contribute to the development and persistence of PTH (29,33,34). TBI, including mTBI, might trigger cortical spreading depression (CSD) at the time of injury and be associated with the extent of brain tissue injury and functional outcomes (35).…”

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

“…Administration of BBG reduced cord damage and improved motor recovery, associated with reduced inflammatory and glial activation, and infiltration (Peng et al, 2009 ). The combination of systemically administered Lom, YM872, and BBG have shown good effects in a rodent model of repeated mild traumatic brain injury and comparable to local delivery at improving outcomes following partial optic nerve transection (Mao et al, 2018 ; Toomey et al, 2019 ). Therefore, future studies should assess the effects of systemic delivery of blood-brain-barrier permeable Lom and YM872 (Nishiyama et al, 1999 ) with BBG, following SCI.…”