Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma

Abstract

BackgroundFollowing partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP.ResultsFollowing partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination.ConclusionsData indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.

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

“…A strong correlation between calpain-related abnormalities in the node of Ranvier and functional deficits has been shown following controlled cortical impact traumatic brain injury [ 82 ] and lateral fluid percussion brain injury [ 83 ]. In line with the authors’ findings in an alternative partial optic nerve transection in vivo model of neurotrauma [ 38 , 39 ], improvements in the integrity of the node of Ranvier shown as preserved nodal length were seen in the injured animals receiving ICI treatment. This is likely due to antagonism of the Ca 2+ dependent calpain cleavage of myelin, thereby protecting against paranodal myelin loop eversion and sheath retraction via YM872-mediated AMPA receptor inhibition.…”

“…Given the consequences of excess Ca 2+ entering neurons and glia after injury, the authors have assessed the effects of a combination of ion channel inhibitors (ICI): Lomerizine (Lom), YM872, and Adenosine 5′-triphosphate periodate oxidized sodium salt (oxATP) to inhibit VGCCs, AMPA receptors, and P2X 7 receptors, respectively. They have shown reductions in excessive Ca 2+ influx and increased neuronal and glial cell viability in vitro using the ICI combination [ 36 ], and reduced oxidative damage, improved myelin structure, and functional recovery following administration of the combinatorial ICI following partial CNS injury in rats [ 37 , 38 , 39 ]. However, the relative inability of oxATP to cross the blood–brain barrier (BBB) and its toxicity to the cardiovascular system limits the clinical application of this compound [ 40 , 41 ].…”

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

“…Nogo-A has been previously identified as a prognostic marker and therapeutic target in ALS due to its substantial expression in motor neuron disease and destabilizing effect on neuromuscular junctions [102,103]. As expected [104,105], elevated Nogo-A expression was associated with evidence of spinal cord injury and increased OPC numbers in this study. In ALS tissues, CTXLP expression was observed in conjunction with elevated Nogo-A in the sheaths, which is expected to limit neurite outgrowth and prevent myelination, coinciding with reduced MAG and MBP expression observed in ALS tissues.…”

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo

“…Extensive characterization of the immune response and associated increased ROS following neurotrauma will help guide the timing of therapeutic intervention following injury for better functional outcomes. There has already been some success in maintaining OPC numbers using multiple ion channel inhibitors following neurotrauma 15 ; however, additional studies assessing the influence of these inhibitors on oxidative damage and differentiation of OPCs are required. It is likely that limiting oxidative damage to oligodendroglia during the acute phase of injury will be associated with improved outcomes in myelin ultrastructure in chronic neurotrauma lesions.…”