Nerve Myelinated Axons Research Articles

Neurofilament Transport Is Bidirectional In Vivo.

Neurofilaments are abundant space-filling cytoskeletal polymers that are transported into and along axons. During postnatal development, these polymers accumulate in myelinated axons causing an expansion of axon caliber, which is necessary for rapid electrical transmission. Studies on cultured nerve cells have shown that axonal neurofilaments move rapidly and intermittently along microtubule tracks in both anterograde and retrograde directions. However, it is unclear whether neurofilament transport is also bidirectional in vivo. Here, we describe a pulse-spread fluorescence photoactivation method to address this in peripheral nerves dissected from hThy1-paGFP-NFM transgenic mice, which express a photoactivatable fluorescent neurofilament protein. Neurofilaments were photoactivated in short segments of myelinated axons in tibial nerves at 2, 4, 8, and 16 weeks of age. The proximal and distal spread of the fluorescence due to the movement of the fluorescent neurofilaments was measured over time. We show that the directional bias and velocity of neurofilament transport can be calculated from these measurements. The directional bias was ∼60% anterograde and 40% retrograde and did not change significantly with age or distance along the nerve. The net velocity decreased with age and distance along the nerve, which is consistent with previous studies using radioisotopic pulse labeling. This decrease in velocity was caused by a decrease in both anterograde and retrograde movement. Thus, neurofilament transport is bidirectional in vivo, with a significant fraction of the filaments moving retrogradely in both juvenile and adult mice.

Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.

Tubulin polyglutamylation is a post-translational modification of the microtubule cytoskeleton, which is generated by a variety of enzymes with different specificities. The "tubulin code" hypothesis predicts that modifications generated by specific enzymes selectively control microtubule functions. Our recent finding that excessive accumulation of polyglutamylation in neurons causes their degeneration and perturbs axonal transport provides an opportunity for testing this hypothesis. By developing novel mouse models and a new glutamylation-specific antibody, we demonstrate here that the glutamylases TTLL1 and TTLL7 generate unique and distinct glutamylation patterns on neuronal microtubules. We find that under physiological conditions, TTLL1 polyglutamylates α-tubulin, while TTLL7 modifies β-tubulin. TTLL1, but not TTLL7, catalyses the excessive hyperglutamylation found in mice lacking the deglutamylase CCP1. Consequently, deletion of TTLL1, but not of TTLL7, prevents degeneration of Purkinje cells and of myelinated axons in peripheral nerves in these mice. Moreover, loss of TTLL1 leads to increased mitochondria motility in neurons, while loss of TTLL7 has no such effect. By revealing how specific patterns of tubulin glutamylation, generated by distinct enzymes, translate into specific physiological and pathological readouts, we demonstrate the relevance of the tubulin code for homeostasis.

The tissue proteome of dorsal root ganglia in Friedreich ataxia

Dorsal root ganglia (DRG) at all levels of the spinal cord are a prominent target of Friedreich ataxia (FA). The lesions include hypoplasia of neurons, proliferation of satellite cells, infiltration by IBA- 1-reactive monocytes, and formation of residual nodules. Paucity and smallness of DRG neurons account for the lack of large myelinated axons in dorsal roots and sensory peripheral nerves. The lack of myelin in dorsal roots can be attributed to low levels of neuregulin 1 type III (NRG1[III]). Lysates of 13 DRG of genetically confirmed FA patients were analyzed by antibody microarray with 878 different validated antibodies that target structural and signaling proteins, and by Western blots. KIT and mTOR, two proteins involved in cellular proliferation, were significantly upregulated in the DRG of FA. KIT is a transmembrane receptor that dimerizes when it binds two molecules of stem cell factor (SCF) in its extracellular domain and becomes activated as protein tyrosine kinase. Immunohistochemistry with anti-KIT generated reaction product in satellite cells of normal DRG and prominent labeling of these cells in FA that co-localized with SCF on double- label immunofluorescence; SCF was present in S100-positive satellite cells rather than monocytes. Immunohistochemical reaction product of mTOR and other mTOR complex proteins, such as hamartin (TSC1), tuberin (TSC2), raptor (mTOR complex 1) and rictor (mTOR complex 2) was also present in satellite cells of normal DRG and DRG of FA. Antibodies to two downstream proteins that are considered to be indicators of mTOR activity, P70 S6K and 4E-binding protein 1, revealed no reaction product in DRG of FA. TSC1, TSC2, and mTOR are best known from their roles in tuberous sclerosis, but expression of these proteins, and KIT, in DRG may contribute to signaling cascades underlying the proliferation of satellite cells in FA.LEARNING OBJECTIVESThis presentation will enable the learner to: 1.Discuss cellular proliferation in the pathogenesis of the DRG lesion in Friedreich ataxiaCONFLICT OF INTERESTAHK is a consultant to PTC Therapeutics of South Plainfield, NJ USA. SP and CS are majority owners of Kinexus.

Low-Intensity Pulsed Ultrasound Prompts Both Functional and Histologic Improvements While Upregulating the Brain-Derived Neurotrophic Factor Expression after Sciatic Crush Injury in Rats

The aim of this study was to determine that low-intensity pulsed ultrasound (LIPUS) at an intensity of 140 mW/cm2 promotes functional and histologic improvements in sciatic nerve crush injury in a rat model and to investigate changes over time in relevant growth factors and receptors, exploring the mechanism of LIPUS in the recovery process after injury. Toe angle in the toe-off phase, regenerative axonal length, myelinated nerve fiber density, diameter of myelinated nerve fiber, axon diameter and myelin sheath thickness were significantly higher in the LIPUS group than in the sham group. Gene and protein expression of brain-derived neurotrophic factor (BDNF) was upregulated in the LIPUS group. In conclusion, LIPUS contributed to rapid functional and histologic improvement and upregulated BDNF expression after sciatic nerve crush injury in rats.

A method to prepare large resin sections for counting myelinated axons in rodent CNS and PNS structures

We present a method that allows preparing histological sections from large blocks of nervous tissue embedded in epoxy resin. Resin-embedding provides excellent resolution especially for the myelin-rich white matter and is often being used for visualizing the myelinated axons in peripheral nerves. However, because of the limited penetration of the reagents, only very small tissue specimens can be processed in this way. Here, we describe a method that enables to embed large specimens and their sectioning on a standard sliding microtome. To process the large specimens, modifications in several steps of the processing technique had to be made. In this paper we demonstrate, that with this technique 1−3 μm thick transversal sections can be prepared from the resin-embedded specimens as large as rat brain hemisphere. Such a large section allows simultaneously: 1.) overviewing and delineating the gross anatomical structures, and 2.) observing the subcellular details at the highest possible optical magnifications. Such a large section with excellent resolution allows application of unbiased stereological methods and reliable quantification of very small objects within the area of interest.

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant ("translational") study design in adult male CMT1A rats for 3months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

In vivo real-time dynamics of ATP and ROS production in axonal mitochondria show decoupling in mouse models of peripheral neuropathies

Mitochondria are critical for the function and maintenance of myelinated axons notably through Adenosine triphosphate (ATP) production. A direct by-product of this ATP production is reactive oxygen species (ROS), which are highly deleterious for neurons. While ATP shortage and ROS levels increase are involved in several neurodegenerative diseases, it is still unclear whether the real-time dynamics of both ATP and ROS production in axonal mitochondria are altered by axonal or demyelinating neuropathies. To answer this question, we imaged and quantified mitochondrial ATP and hydrogen peroxide (H2O2) in resting or stimulated peripheral nerve myelinated axons in vivo, using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. We found that ATP and H2O2 productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H2O2 productions but with different dynamics: ROS production peaked shortly and transiently after the stimulation while ATP production increased gradually for a longer period of time. In neuropathic MFN2R94Q mice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity. However, elevated H2O2 production was largely sustained. Finally, inducing demyelination with lysophosphatidylcholine resulted in a reduced level of ATP while H2O2 level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity.

Functional evaluation outcomes correlate with histomorphometric changes in the rat sciatic nerve crush injury model: A comparison between sciatic functional index and kinematic analysis.

Elucidating whether there is a correlation between biomechanical functions and histomorphometric data in the rat sciatic nerve crush injury model would contribute to an accurate evaluation of the regeneration state without sacrificing animals. The gold standard for functional evaluation is the sciatic functional index (SFI) despite there being intrinsic shortcomings. Kinematic analysis is considered a reliable and sensitive approach for functional evaluation, most commonly assessed as ankle angle at various phases of a gait cycle. Studies utilizing the toe angle for functional evaluation are scarce, and changes in the toe angle following surgery remain unknown. The present study assessed correlations of ankle angle, toe angle and SFI with histomorphometric data, aiming to determine which parameters most accurately reflect changes in histomorphometric data over time. Six Lewis rats were designated as the control group. 30 animals received surgery, six of them were randomly selected on the first, second, third, fourth, and sixth week after surgery for measurements of ankle and toe angles in the “toe-off” phase, and for evaluation of SFI. Histomorphometric analysis were also performed, to determine the number of myelinated nerve fibers, diameters of myelinated nerve fibers, axon diameters, and myelin sheath thicknesses. Furthermore, we investigated changes in ankle angle, toe angle, SFI, and histomorphometric data over time, as well as correlations between ankle angle, toe angle, and SFI with histomorphometric data. The results revealed that changes in SFI, ankle angle, and toe angle highly correlate with histomorphometric data in the rat sciatic nerve crush injury model. Toe angle reflected changes in histomorphometric data with time more precisely than ankle angle or SFI did, and ankle angle was a better prognostic parameter than SFI.

A collagen-coated PGA conduit for interpositional-jump graft with end-to-side neurorrhaphy for treating facial nerve paralysis in rat.

This study investigated the potential of collagen-coated polyglycolic acid (PGA) tube with interpositional jump graft (IPJG) in rat. A total of 16 Lewis rats were used in this study. Facial nerve paralysis was created by ligating facial nerve trunk with a ligature clip. The rats were divided into 3 groups. Nerve conduit group (n = 6) were treated by IPJG with collagen-coated PGA tubes between the facial nerve trunks and the hypoglossal nerves. Autograft group (n = 6) were treated by IPJG with the greater auricular nerves. As the control group (n = 4), non-treated-model rats with facial nerve paralysis were used. The number of myelinated fibers, fiber diameter, axon diameter, myelin thickness, and g-ratio, were analyzed histologically at 13 weeks after surgery. Compound muscle action potential (CMAP) and retrograde tracing were measured. Although the number of myelinated fibers in autograft group (1957 ± 775) had significantly higher than that of nerve conduit group (90 ± 41, P < .05), the nerve conduit group showed the regeneration of myelinated nerve axons. CMAP amplitude values of the autograft (4706 ± 1154 µV) and the nerve conduit groups (4119 ± 1397 µV) were significantly higher than that of the control group (915 ± 789 µV, P < .05). Retrograde tracing confirmed the double innervation of mimetic muscles by the facial and hypoglossal nucleus in both groups. This study showed histologically and physiologically the superior effectiveness of performing IPJG with a collagen-coated PGA conduit in a rat model.

Effect of Methyl Mercury on the Cerebellar Cortex of Rats and the Possible Neuroprotective Role of Mesenchymal Stem Cells Conditioned Medium. Histological and Immunohistochemical Study

BACKGROUND: Methyl mercury (Me Hg) is an environmental toxin associated with many serious neurological disorders. Conditioned Medium (CM) derived from Mesenchymal Stem Cells (MSCs) is a novel promising approach for the treatment of nervous system damage and various diseases. OBJECTIVE: The aim of this research is to assess the consequence of Me Hg on the rats’ cerebellar cortex and the potential neuroprotective effect of MSCs – CM. MATERIALS AND METHODS: Forty adult male albino rats were divided into four groups: Group I: control rats; Group II: Me Hg chloride treated rats; Group III: Me Hg chloride and DMEM treated rats; Group IV: CM treated rats after injection with Me Hg chloride. Cerebellar specimens were taken and handled for histological and immunohistochemical techniques. Morphometrical studies and statistical analysis were performed. RESULTS: Groups II and III showed various changes such as neuronal degeneration and apoptosis. The mean number of Purkinje cells was significantly decreased (P<0.01), while Glial Fibrillary Acidic Protein (GFAP) immunostaining was significantly increased (P<0.01) in the neuroglial cells. Ultrastructural examination showed thinning and apparent decrease in the number of myelinated nerve axons. Shrunken Purkinje cells were observed with irregular nuclei, heterogenous cytoplasm, and disrupted mitochondria. Group IV showed improvement of the histological and electron microscopic changes defined in groups II and III. CONCLUSION: Me Hg exposure led to degenerative changes on cerebellar cortex. MSCs – CM is a very promising approach and has neuroprotective effects.

The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis.

Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 μm (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 µm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

Chitosan nerve conduits seeded with autologous bone marrow mononuclear cells for 30\u2009mm goat peroneal nerve defect

In the current research, to find if the combination of chitosan nerve conduits seeded with autologous bone marrow mononuclear cells (BM-MNCs) can be used to bridge 30 mm long peroneal nerve defects in goats, 15 animals were separated into BM-MNC group (n = 5), vehicle group (n = 5), and autologous nerve graft group (n = 5). 12 months after the surgery, animals were evaluated by behavioral observation, magnetic resonance imaging tests, histomorphological and electrophysiological analysis. Results revealed that animals in BM-MNC group and autologous nerve graft group achieved fine functional recovery; magnetic resonance imaging tests and histomorphometry analysis showed that the nerve defect was bridged by myelinated nerve axons in those animals. No significant difference was found between the two groups concerning myelinated axon density, axon diameter, myelin sheath thickness and peroneal nerve action potential. Animals in vehicle group failed to achieve significant functional recovery. The results indicated that chitosan nerve conduits seeded with autologous bone marrow mononuclear cells have strong potential in bridging long peripheral nerve defects and could be applied in future clinical trials.

Tolerability and efficacy study of P2X7 inhibition in experimental Charcot-Marie-Tooth type 1A (CMT1A) neuropathy

Charcot-Marie-Tooth 1A (CMT1A) is a demyelinating hereditary neuropathy for which pharmacological treatments are not yet available. An abnormally high intracellular Ca2+ concentration was observed in Schwann cells (SC) from CMT1A rats, caused by the PMP22-mediated overexpression of the P2X7 purinoceptor. The purpose of this study was to investigate the tolerability and therapeutic potential of a pharmacological antagonist of the P2X7 receptor (A438079) in CMT1A. A438079 ameliorated in vitro myelination of organotypic DRG cultures from CMT1A rats. Furthermore, we performed an experimental therapeutic trial in PMP22 transgenic and in wild-type rats. A preliminary dose-escalation trial showed that 3mg/kg A438079 administered via intraperitoneal injection every 24h for four weeks was well tolerated by wild type and CMT1A rats. Affected rats treated with 3mg/kg A438079 revealed a significant improvement of the muscle strength, when compared to placebo controls. Importantly, histologic analysis revealed a significant increase of the total number of myelinated axons in tibial nerves. Moreover, a significant decrease of the hypermyelination of small caliber axons and a significant increase of the frequency and diameter of large caliber myelinated axons was highlighted. An improved distal motor latencies was recorded, whereas compound muscle action potentials (CMAP) remained unaltered. A438079 reduced the SC differentiation defect in CMT1A rats. These results show that pharmacological inhibition of the P2X7 receptor is well tolerated in CMT1A rats and represents a proof-of-principle that antagonizing this pathway may correct the molecular derangements and improve the clinical phenotype in the CMT1A neuropathy.

Ascorbic Acid and Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease type 1A (CMT1A) is a disease for which no drug treatments are available. Passage et al. reported that ascorbic acid reduced the mRNA level of PMP22, improved motor function and increased the numbers of myelinated peripheral nerve axons in a mouse model of CMT1A. Based on these results, five clinical trials were undertaken at different centers worldwide. However, none of them demonstrated significant effectiveness. Although these outcomes were disappointing, these studies have provided many useful insights for conducting the next randomised controlled trial for CMT1A.

Mitochondrial morphology differences and mitophagy deficit in murine glaucomatous optic nerve.

Decreased ATP correlates with intraocular pressure exposure in the optic nerves of mice with glaucoma. To understand what underlies this energy deficit, we examined mitochondria in the myelinated optic nerve axons of the DBA/2J mouse, a model of glaucoma secondary to iris pigment disease, and the DBA/2(wt-gpnmb) control strain. Mitochondrial length, width, surface area, and health status were measured in 30 electron microscopic fields within the myelinated portion of optic nerves from DBA/2J and DBA/2(wt-gpnmb) mice at 3, 6, and 10 months of age. Protein was isolated from optic nerve for analysis of PINK1, Parkin, LC3-I and -II, and lysosome-associated membrane protein 1 (LAMP1) by Western blot. The number of mitochondria in DBA/2J optic nerve was increased, and they had significantly smaller surface area. Mitochondria in DBA/2J were closer to the axolemma, more spatially isolated, and their cristae were more disrupted at every age group as compared to DBA/2(wt-gpnmb). Autophagosomes were significantly increased in DBA/2J optic nerve at all ages. Protein analysis showed higher LC3-II to LC3-I ratio in aged DBA/2J optic nerve than in DBA/2(wt-gpnmb). PINK1 and Parkin levels were not statistically different across age groups. LAMP1 was significantly decreased in the aged DBA/2J optic nerve. Decreased surface area, combined with reduced oxidative capacity in mitochondria from the aged DBA/2J axon, indicate that mitochondrial pathology may contribute to the energy deficit in glaucomatous optic nerve. Though autophagosomes were increased in DBA/2J optic nerve, the increased mitochondria and decreased LAMP1 suggest deteriorating mitochondria are not being efficiently recycled by mitophagy.

Computational methods for a mathematical model of propagation of nerve impulses in myelinated axons

This paper is concerned with the approximate solution of a nonlinear mixed type functional differential equation (MTFDE) arising from nerve conduction theory. The equation considered describes conduction in a myelinated nerve axon. We search for a monotone solution of the equation defined in the whole real axis, which tends to given values at ±∞. We introduce new numerical methods for the solution of the equation, analyse their performance, and present and discuss the results of the numerical simulations.

The node of Ranvier in multifocal motor neuropathy.

Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction block, and antibodies against ganglioside GM1 which is expressed on the axolemma of nodes of Ranvier and perinodal Schwann cells. Treatment by regular IVIg courses results in temporary improvement but cannot prevent slowly progressing weakness due to axonal degeneration. This review discusses possible mechanisms of conduction block and the reasons why motor axons are selectively affected in this disorder.

The neurobiology of predation: sensory adaptations to carnivory (89.3)

Study objective: We investigated the central and peripheral nervous systems of northern grasshopper mice (Onychomys leucogaster), the most highly carnivorous rodents in North America, in order to explore potential neural correlates of the transition to carnivory.Methods: Multiunit electrophysiological recordings combined with analysis of flattened sections of neocortex processed for cytochrome oxidase were used to determine the topography of primary somatosensory cortex (S1) and the location and size of both the visual and auditory cortex. These findings were then related to flattened cortical sections of juvenile grasshopper mice labeled with the serotonin transporter (SERT) antibody. The number of myelinated axons in trigeminal, cochlear, and optic nerves were also quantified.Results: An enlarged forepaw representation was discovered within S1. Primary visual cortex (V1) also appeared to be larger in flattened cortex preparations compared to other rodents. Whereas the trigeminal and cochlear nerves were comparable to other rodents, the optic nerve contained a large number of axons.Conclusions: Grasshopper mice utilize a more specialized repertoire of attacks that rely on the forelimb, which perhaps corresponds to a magnification of this representation in S1 relative to other rodents. Enlargements of the optic nerve and V1 may also optimize processing of visual cues to enhance predatory success.Grant Funding Source: Supported by NIH grant # DE016061 and NSF grant # 0844743 to K.C.C.

Involvement of Nax sodium channel in peripheral nerve regeneration via lactate signaling.

Na(x), a sodium concentration-sensitive sodium channel, is expressed in non-myelinating Schwann cells of the adult peripheral nervous system, but the pathophysiological role remains unclear. We found that functional recovery of the hind paw responses from the sciatic nerve transection was delayed in Na(x) knockout (Na(x)⁻/⁻) mice. Histological analyses showed a decrease in the number of regenerated myelinated axons in (Na(x)⁻/⁻) sciatic nerves. The delay in the recovery in Na(x)⁻/⁻ mice was improved by lactate and inhibited by a monocarboxylate transporter inhibitor. In vitro experiments using cultured Schwann cells showed that lactate release was enhanced by endothelin (ET)-1 and blocked by an ET receptor type B antagonist. Here, it is conceivable that Na(x) was activated by ET-1. The amount of lactate release by ET-1 was lower in Na(x)⁻/⁻ mice than in wild-type mice. These results indicated that Na(x) is functionally coupled to ET for lactate release via ET receptor type B and is involved in peripheral nerve regeneration.

Nuclear factor‐κB activation in schwann cells regulates regeneration and remyelination

Schwann cells (SCs) are crucial for peripheral nerve development and regeneration; however, the intrinsic regulatory mechanisms governing postinjury responses are poorly understood. Activation and deacetylation of nuclear factor-κB (NF- κB) in SCs have been implicated as prerequisites for peripheral nerve myelination. Using GFAP-IκBα-dn mice in which NF- κB transcriptional activation is inhibited in SCs, we found no discernable differences in the quantity or structure of myelinated axons in adult facial nerves. Following crush injury, axonal regeneration was impaired at 31 days and significantly enhanced at 65 days in transgenic animals. Compact remyelination and Remak bundle organization were significantly compromised at 31 days and restored by 65 days post injury. Together, these data indicate that inhibition of NF-κB activation in SCs transiently delays axonal regeneration and compact remyelination. Manipulating the temporal activation of nuclear factor-κB in Schwann cells may offer new therapeutic avenues for PNS and CNS regeneration.