Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo.

In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma

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

Background: 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. Changes in Ca 2+ 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 Ca 2+ channel inhibitor Lomerizine (Lom), the Ca 2+ permeable AMPA receptor inhibitor YM872 and the P2X 7 receptor inhibitor oxATP. Results: Following 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. Conclusions: Data 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

Oligodendrocytes: biology and pathology

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They are the end product of a cell lineage which has to undergo a complex and precisely timed program of proliferation, migration, differentiation, and myelination to finally produce the insulating sheath of axons. Due to this complex differentiation program, and due to their unique metabolism/physiology, oligodendrocytes count among the most vulnerable cells of the CNS. In this review, we first describe the different steps eventually culminating in the formation of mature oligodendrocytes and myelin sheaths, as they were revealed by studies in rodents. We will then show differences and similarities of human oligodendrocyte development. Finally, we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases, and we will reveal the different principles leading to the restoration of myelin sheaths or to a failure to do so

Up-Regulation of Oligodendrocyte Lineage Markers in the Cerebellum of Autistic Patients: Evidence from Network Analysis of Gene Expression

Autism is a neurodevelopmental disorder manifested by impaired social interaction, deficits in communication skills, restricted interests, and repetitive behaviors. In neurodevelopmental, neurodegenerative, and psychiatric disorders, glial cells undergo morphological, biochemical, and functional rearrangements, which are critical for neuronal development, neurotransmission, and synaptic connectivity. Cerebellar function is not limited to motor coordination but also contributes to cognition and may be affected in autism. Oligodendrocytes and specifically oligodendroglial precursors are highly susceptible to oxidative stress and excitotoxic insult. In the present study, we searched for evidence for developmental oligodendropathy in the context of autism by performing a network analysis of gene expression of cerebellar tissue. We created an in silico network model (OLIGO) showing the landscape of interactions between oligodendrocyte markers and demonstrated that more than 50 % (16 out of 30) of the genes within this model displayed significant changes of expression (corrected p valu

Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular events that result in a period of secondary damage that can last for months after the initial trauma. The ensuing outcome of these prolonged cellular perturbations is the induction of neuronal and glial cell death through excitotoxic mechanisms and subsequent free radical production. We have previously shown that astrocytes can directly induce oligodendrocyte death following trauma, but the mechanisms regulating this process within the oligodendrocyte remain unclear. Here we provide evidence demonstrating that astrocytes directly regulate oligodendrocyte death after trauma by inducing activation of NADPH oxidase within oligodendrocytes. Spinal cord injury resulted in a significant increase in oxidative damage which correlated with elevated expression of the gp91 phox subunit of the NADPH oxidase enzyme. Immunohistochemical analysis confirmed the presence of gp91 phox in oligodendrocytes in vitro and at 1 week following spinal cord injury. Exposure of oligodendrocytes to media from injured astrocytes resulted in an increase in oligodendrocyte NADPH oxidase activity. Inhibition of NADPH oxidase activation was sufficient to attenuate oligodendrocyte death in vitro and at 1 week following spinal cord injury, suggesting that excitotoxicity of oligodendrocytes after trauma is dependent on the intrinsic activation of the NADPH oxidase enzyme. Acute administration of the NADPH oxidase inhibitor apocynin and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate channel blocker 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione significantly improved locomotor behavior and preserved descending axon fibers following spinal cord injury. These studies lead to a better understanding of oligodendrocyte death after trauma and identify potential therapeutic targets in disorders involving demyelination and oligodendrocyte death