Increase In Myelin Thickness Research Articles

An electrospun nerve wrap comprising Bletilla striata polysaccharide with dual function for nerve regeneration and scar prevention

Peripheral nerve injuries mainly occur in the extremities and result in functional deficits, and recovery after microsurgical repair is slow (<1 mm/day) and frustrating. To improve the results of nerve repair, it is crucial to promote local Schwann cell (SC) function, neurite outgrowth, and to reduce perineural adhesion. In this study, a nerve wrap electrospun with Bletilla striata polysaccharide (BSP) and waterborne polyurethane (WPU) was designed to wrap around the repaired nerve to achieve the goal. In SC proliferation/migration tests and neurite outgrowth assay, BSP/WPU revealed considerable improvement. In rabbit sciatic nerve repair model, BSP/WPU exhibited significantly higher compound muscle action potential, muscle contraction force, and reduced perineural adhesion. The downstream fascicles of the BSP/WPU group exhibited a 50 % increase in diameter and 100 % increase in myelin thickness compared with the control group. In vitro and in vivo experiments indicated the positive effect of BSP/WPU nerve wrap on nerve regeneration.

Beneficial Effect of (‐)‐epigallocatechin‐3‐gallate (EGCG) on Sciatic Nerve Crush Injury: Stereological analysis

The neuroprotective effect of EGCG on sciatic nerve crush injury is associated with significant neurobehavioral recovery (Renno et al. 2014). In this study, we examined the histological changes in the sciatic nerve after crush injury following EGCG treatment. The mean cross sectional area of the axon showed a significant increase in the EGCG treated group starting at week 4 and continued up to week 8 compared to CRUSH animals. However, axon area remained much smaller in CRUSH+EGCG and CRUSH groups compared to SHAM and NAIVE animals. The number of axons per unit area was significantly decreased in CRUSH+EGCG and CRUSH groups compared to control. The CRUSH group displayed a significant increase in total small and thinly myelinated axon number at week 6 and 8 post‐injury. ECGC treated animals showed a significant decrease in the total myelinated axon numbers. CRUSH+EGCG group showed a significant increase in myelin thickness in the distal sciatic nerve segment at week 4 till week 8 compared to CRUSH animals. EGCG treatment significantly increased the fiber diameter to axon diameter (F/A) ratio and the myelin thickness to axon diameter (M/A) ratio starting at week 2 post sciatic nerve injury compared to CRUSH animals. EGCG has profound positive effect on the myelinated axons; increase in the axon area, myelin thickness, F/A ratio and M/A ratio. In summary, quantitative stereological evaluation revealed significant histomorphological evidence of neuroregeneration in the sciatic nerve of CRUSH+EGCG rats compared to control groups between 2 and 4 weeks postoperatively. The morphometric data analysis supports our hypothesis that EGCG treatment stimulates regeneration of myelinated axons and minimizes histomorphological alterations caused by crush injury of sciatic nerve.This work was supported by Kuwait University Research Administration (grant No. MA01/11).

DDIT4/REDD1/RTP801 Is a Novel Negative Regulator of Schwann Cell Myelination

Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and negatively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination. We show that DDIT4 is expressed in Schwann cells and its maximum expression level precedes the peak of AKT activation and of DLG1 activity in peripheral nerves. Moreover, loss of DDIT4 expression both in vitro and in vivo in Ddit4-null mice provokes sustained hypermyelination and enhanced mTORC1 activation, thus suggesting that this molecule is a novel negative regulator of PNS myelination.

Effect of white adipose tissue flap and insulin‐like growth factor‐1 on nerve regeneration in rats

Adipose tissue-derived stem cells and insulin-like growth factor-1 (IGF-1) have shown potential to enhance peripheral nerve regeneration. The purpose of this study was to investigate the effect of an in vivo biologic scaffold, consisting of white adipose tissue flap (WATF) and/or IGF-1 on nerve regeneration in a crush injury model. Forty rats all underwent a sciatic nerve crush injury and then received: a pedicled WATF, a controlled local release of IGF-1, both treatments, or no treatment at the injury site. Outcomes were the normalized maximum isometric tetanic force (ITF) of the tibialis anterior muscle and histomorphometric measurements. At 4 weeks, groups with WATF had a statistically significant improvement in maximum ITF recovery, as compared to those without (P < 0.05), and there was an increase in myelin thickness and total axon count in the WATF-only group versus control (P < 0.01). Functional and histomorphometric data suggest that IGF-1 suppressed the effect of the WATF. Use of a pedicled WATF improved the functional and histomorphometrical results after axonotmesis in a rat model. IGF-1 does not appear to enhance nerve regeneration in this model. Utilizing the WATF may have a beneficial therapeutic role in peripheral nerve injuries.

Behavioral assessment of visual deficits in the taiep mutant.

Taiep (tremor, ataxia, immobility, epilepsy, paralysis) mutants show a significant increase in myelin thickness from 10 to 30 days of age but then demonstrate a decrease in myelin thickness from 1 to 6 months. The severity of the demyelination in the optic nerve suggests that visual deficits may exist in the taiep mutants. Animals were trained on a discrimination task, in which responses to a light stimulus (the SD period) were reinforced on a fixed ratio (FR)-1 schedule, and responses in the absence of the light stimulus (the SΔ period) were not reinforced. Following training, the light intensity presented during the SD period was gradually reduced between sessions until -6.0 candela/m2 was reached. Both groups of animals - taiep mutants and control Sprague Dawley rats - successfully recognized and responded in the presence of the stimulus near perfectly by the final day of training, suggesting that taiep mutants demonstrated normal learning, at least under this paradigm. Despite the severe demyelination of the taiep optic nerve, no visual deficits were detected as both groups of animals performed similarly as the light intensity decreased. Though the myelin loss of the optic nerve may have negatively affected signal transduction, this did not result in an increase in visual threshold.

Could Sex Differences in White Matter be Explained by g ratio?

Recent studies with magnetic resonance imaging suggest that age-related changes in white matter during male adolescence may indicate an increase in g ratio wherein the radial growth of an axon outpaces a corresponding increase in myelin thickness. We review the original Rushton (1951) model where a g ratio of ∼0.6 represents an optimal relationship between the axon and fibre diameters vis-à-vis conduction velocity, and point out evidence indicating slightly higher g ratio in large-diameter fibres. We estimate that fibres with a diameter larger than 9.6 μm will have a relatively thinner myelin sheath, and brains with increasingly larger proportions of such large-diameter fibres will have progressively lower concentration of myelin. We conclude by pointing out possible implications of “suboptimal” g ratio for the emergence of “disconnection” disorders, such as schizophrenia, in late adolescence.

FGF plays a subtle role in oligodendrocyte maintenance in vivo

Numerous in vitro studies indicate that fibroblast growth factors (FGFs) play a role in both the development and maintenance of oligodendrocytes. Addition of FGF to mature oligodendrocytes in culture was reported to downregulate the expression of genes encoding proteins of the myelin sheath and to induce a loss of myelin compaction. In this study, a model was developed to functionally block FGF signaling in oligodendrocytes in vivo, by generating transgenic mice expressing a dominant-negative FGF receptor (FGFR1), under the control of the myelin basic protein (MBP) promoter. To demonstrate the effectiveness of this model, truncated FGFR1 was first overexpressed in an FGF-responsive cell line in vitro. It was confirmed that FGF-signalling was blocked in these cells. Subsequently, five independent transgenic lines ("MBP-FRD") were generated. Three lines expressing the highest level of the transgene were further studied. Initial investigation by Western blot and light microscopic analyses revealed no apparent alterations in myelination of the MBP-FRD mouse brains. However, ultrastructural analysis of myelinated optic nerve fibres from two independent MBP-FRD lines revealed a significant increase in myelin thickness as a function of fibre diameter for both transgenic lines (13% and 16% increase). This increase in myelin thickness was not accompanied by alterations in myelin compaction. These results support the idea that FGF signaling in oligodendrocytes plays a role in the modulation of axon myelination in vivo.