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.
Highlights
Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function
We have demonstrated that the three ion channel inhibitors in combination were required to preserve myelin compaction, node of Ranvier length and behavioural function, in optic nerve vulnerable to secondary degeneration in the chronic phase, 3 months following injury [49]
Disruptions to axonal and oligodendrocyte proteins in secondary degeneration Structural axonal and oligodendrocyte proteins were examined in ventral optic nerve vulnerable to secondary degeneration, following partial optic nerve transection
Summary
Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Following trauma to the central nervous system (CNS), cells beyond the initial injury site succumb to. Changes in Ca2+ flux occur following neurotrauma [3], and in optic nerve vulnerable to secondary degeneration following partial transection [4, 5]. Altered Ca2+ flux is associated with increased reactive oxygen species (ROS), enhanced anti-oxidant activity, and oxidative damage to DNA, protein and lipid in the first minutes and days following injury [6,7,8]. Ca2+ enters cells of the CNS through a range of channels and receptors, including but not limited to: voltage-gated C a2+ channels (VGCCs) [11]; purinergic P 2X7 receptors (P2X7Rs) [12]; and Ca2+ permeable ionotropic α-amino-3-hydroxy-5-methyl-4-. Increasing extracellular ATP concentrations are a typical consequence of injury [17], leading to increased Ca2+ flux through P 2X7Rs [18]
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