Thrombin regulates the ability of Schwann cells to support neuritogenesis and to maintain the integrity of the nodes of Ranvier

Schwann cells (SC) are characterized by a remarkable plasticity that enables them to promptly respond to nerve injury promoting axonal regeneration. In peripheral nerves after damage SC convert to a repair-promoting phenotype activating a sequence of supportive functions that drive myelin clearance, prevent neuronal death, and help axon growth and guidance. Regeneration of peripheral nerves after damage correlates inversely with thrombin levels. Thrombin is not only the key regulator of the coagulation cascade but also a protease with hormone-like activities that affects various cells of the central and peripheral nervous system mainly through the protease-activated receptor 1 (PAR1). Aim of the present study was to investigate if and how thrombin could affect the axon supportive functions of SC. In particular, our results show that the activation of PAR1 in rat SC cultures with low levels of thrombin or PAR1 agonist peptides induces the release of molecules, which favor neuronal survival and neurite elongation. Conversely, the stimulation of SC with high levels of thrombin or PAR1 agonist peptides drives an opposite effect inducing SC to release factors that inhibit the extension of neurites. Moreover, high levels of thrombin administered to sciatic nerve ex vivo explants induce a dramatic change in SC morphology causing disappearance of the Cajal bands, enlargement of the Schmidt-Lanterman incisures and calcium-mediated demyelination of the paranodes. Our results indicate thrombin as a novel modulator of SC plasticity potentially able to favor or inhibit SC pro-regenerative properties according to its level at the site of lesion

Neurotoxicity

Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic diseases in humans, and many more are used as experimental tools to disturb or damage the nervous system of animals. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Some disrupt neural function, others induce maldevelopment or damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects

Quantitative Ultrasound and B-mode Image Texture Features Correlate with Collagen and Myelin Content in Human Ulnar Nerve Fascicles

We investigate the usefulness of quantitative ultrasound (QUS) and B-mode texture features for characterization of ulnar nerve fascicles. Ultrasound data were acquired from cadaveric specimens using a nominal 30 MHz probe. Next, the nerves were extracted to prepare histology sections. 85 fascicles were matched between the B-mode images and the histology sections. For each fascicle image, we selected an intra-fascicular region of interest. We used histology sections to determine features related to the concentration of collagen and myelin, and ultrasound data to calculate backscatter coefficient (-24.89 dB $\pm$ 8.31), attenuation coefficient (0.92 db/cm-MHz $\pm$ 0.04), Nakagami parameter (1.01 $\pm$ 0.18) and entropy (6.92 $\pm$ 0.83), as well as B-mode texture features obtained via the gray level co-occurrence matrix algorithm. Significant Spearman's rank correlations between the combined collagen and myelin concentrations were obtained for the backscatter coefficient (R=-0.68), entropy (R=-0.51), and for several texture features. Our study demonstrates that QUS may potentially provide information on structural components of nerve fascicles

Differential binding patterns of anti-sulfatide antibodies to glial membranes

Sulfatide is a major glycosphingolipid in myelin and a target for autoantibodies in autoimmune neuropathies. However neuropathy disease models have not been widely established, in part because currently available monoclonal antibodies to sulfatide may not represent the diversity of anti-sulfatide antibody binding patterns found in neuropathy patients. We sought to address this issue by generating and characterising a panel of new anti-sulfatide monoclonal antibodies. These antibodies have sulfatide reactivity distinct from existing antibodies in assays and in binding to peripheral nerve tissues and can be used to provide insights into the pathophysiological roles of anti-sulfatide antibodies in demyelinating neuropathies

Dysregulation of NAD+ metabolism induces a Schwann cell dedifferentiation program

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NA

Acute- and late-phase matrix metalloproteinase (MMP)-9 activity is comparable in female and male rats after peripheral nerve injury.

BACKGROUND:In the peripheral nerve, pro-inflammatory matrix metalloproteinase (MMP)-9 performs essential functions in the acute response to injury. Whether MMP-9 activity contributes to late-phase injury or whether MMP-9 expression or activity after nerve injury is sexually dimorphic remains unknown. METHODS:Patterns of MMP-9 expression, activity and excretion were assessed in a model of painful peripheral neuropathy, sciatic nerve chronic constriction injury (CCI), in female and male rats. Real-time Taqman RT-PCR for MMP-9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) of nerve samples over a 2-month time course of CCI was followed by gelatin zymography of crude nerve extracts and purified MMP-9 from the extracts using gelatin Sepharose-beads. MMP excretion was determined using protease activity assay of urine in female and male rats with CCI. RESULTS:The initial upsurge in nerve MMP-9 expression at day 1 post-CCI was superseded more than 100-fold at day 28 post-CCI. The high level of MMP-9 expression in late-phase nerve injury was accompanied by the reduction in TIMP-1 level. The absence of MMP-9 in the normal nerve and the presence of multiple MMP-9 species (the proenzyme, mature enzyme, homodimers, and heterodimers) was observed at day 1 and day 28 post-CCI. The MMP-9 proenzyme and mature enzyme species dominated in the early- and late-phase nerve injury, consistent with the high and low level of TIMP-1 expression, respectively. The elevated nerve MMP-9 levels corresponded to the elevated urinary MMP excretion post-CCI. All of these findings were comparable in female and male rodents. CONCLUSION:The present study offers the first evidence for the excessive, uninhibited proteolytic MMP-9 activity during late-phase painful peripheral neuropathy and suggests that the pattern of MMP-9 expression, activity, and excretion after peripheral nerve injury is universal in both sexes