Peripheral Nerve Degeneration Research Articles

Arsenic Neurotoxicity in Humans.

Arsenic (As) contamination affects hundreds of millions of people globally. Although the number of patients with chronic As exposure is large, the symptoms and long-term clinical courses of the patients remain unclear. In addition to reviewing the literature on As contamination and toxicity, we provide useful clinical information on medical care for As-exposed patients. Further, As metabolite pathways, toxicity, speculated toxicity mechanisms, and clinical neurological symptoms are documented. Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers. A sural nerve biopsy showed the axonal degeneration of peripheral nerves mainly in small myelinated and unmyelinated fibers. Exposure to high concentrations of As causes severe central nervous system impairment in infants, but no or minimal impairment in adults. The exposure dose–response relationship was observed in various organs including neurological systems. The symptoms caused by heavy metal pollution (including As) are often nonspecific. Therefore, in order to recognize patients experiencing health problems caused by As, a multifaceted approach is needed, including not only clinicians, but also specialists from multiple fields.

Inhibition of Neuronal Nitric Oxide Synthase by Ethyl Pyruvate in Schwann Cells Protects Against Peripheral Nerve Degeneration.

Schwann cells are essential glial cells in the peripheral nervous system (PNS), and dysfunction of Schwann cells can induce various peripheral neurodegenerative diseases. Oxidative stress has been implicated as a causative factor in degenerative nerve diseases; however, there no effective molecules are available to inhibit nerve degeneration in peripheral neurodegenerative diseases. Ethyl pyruvate (EP) is a candidate regulator of oxidative stress, targeting Schwann cells during peripheral nerve degeneration. Here, we investigated the effects of EP on axonal degradation, demyelination, transcriptional regulation, and macrophage recruitment during Wallerian degeneration of the sciatic nerve, ex vivo and in vivo. EP prevented the expression of neuronal nitric oxide synthase (NOS1), but not that of inducible nitric oxide synthase (NOS2), during Wallerian degeneration. These results suggest that effect of EP on Schwann cells may protect against peripheral nerve degeneration through its NOS1-specific regulation.

Chiral Brønsted acid-catalyzed Friedel–Crafts reaction of 3-indolylsulfamidates with indoles: Synthesis of enantioenriched bisindolylmethane sulfamates

A Brønsted acid-catalyzed asymmetric Friedel–Crafts alkylation of 3-indolylsulfamidates with indoles has been established toward the efficient synthesis of biologically important bisindolylarylmethane derivatives containing the phenylsulfamate group. The reaction using chiral BINOL-derived phosphoric acid as the catalyst was tolerant to a diverse range of 3-indolylsulfamates and indoles, and provided for the first time bisindolylarylmethane sulfamate derivatives in good yields and with moderate to high enantioselectivities (up to 89% yield, 94:6 er). Moreover, some of these novel compounds were evaluated for their biological activities and confirmed to show bioactivity for preventing peripheral nerve degeneration.

Time Course of Axon and Myelin Degeneration in Peripheral Nerves in Experimental Autoimmune Neuritis Rats

Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.

The natural plant flavonoid apigenin is a strong antioxidant that effectively delays peripheral neurodegenerative processes.

Oxidative stress contributes to the progression of neurodegenerative diseases of the central and peripheral nervous systems, including Alzheimer's disease, Parkinson's disease, stroke, and diabetic neuropathy. Despite the greater capability of peripheral nerves to regenerate compared with those in the brain or spinal cord, chronic oxidative stress leads to irreversible neurodegeneration in peripheral nerves. Thus, many efforts have been made to defend against irreversible peripheral nerve degeneration and oxidative stress. Numerous phytochemicals have been revealed as antioxidants which neutralize free radicals and reduce peripheral neurocellular damage. Among them, polyphenols alleviate neurodegeneration by interacting with reactive oxygen species. Apigenin is a polyphenol found in plant-derived foods, including parsley, thyme, celery, and chamomile tea. Apigenin has been reported to exert antioxidative effects by scavenging free radicals. In particular, apigenin has a neuroprotective effect against oxidative stress in neurological disorders, such as cerebral ischemia. However, to date, no studies have shown an association of the inhibitory effect of apigenin with peripheral nerve degeneration. In this work, we showed that apigenin has a neuroprotective effect against peripheral nerve degeneration according to four key phenotypes: axonal degradation, myelin fragmentation, trans-dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated kinase-independent processes. Thus, apigenin could be a good candidate to treat peripheral neurodegenerative diseases.

The Neuroprotective Effects of Micronized PEA (PEA‐m) Formulation on Diabetic Neuropathy in Mice

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and is associated with significant morbidity and mortality. DPN is characterized by progressive, distal‐to‐proximal degeneration of peripheral nerves that leads to pain, weakness, and eventual loss of sensation. The pathophysiology of DPN includes a complex network of unified vascular, metabolic and neurotropic defects, in particular, involves oxidative and nitrosative stress, neuroinflammation, microvascular ischemia, inflammatory infiltrates, impaired angiogenesis within peripheral nerve tissue, neuroanatomical changes, including decreases in nerve conduction velocity and altered activity of the nervous fiber enzyme Na+, K+‐ATPase, which determines endoneurial edema formation and reactive oxygen species (ROS) release. Accumulation of ROS increases lipid, DNA, and protein peroxidation, induces cellular apoptosis and reduces nerve blood flow. Increased oxidative stress leads to activation of the poly ADP ribose polymerase (PARP) pathway which regulates the gene expressions involved in inflammatory reactions and neural dysfunction. Activated mast cells contribute directly to neuropathic pain by releasing algogenic mediators after degranulation. Mast cells and nerve growth factor (NGF) appear involved in neuroimmune interactions and tissue inflammation. NGF exerts a modulatory role on sensory nociceptive nerve physiology, which appears to correlate with hyperalgesic phenomena occurring in tissue inflammation.Mouse models of type 1 or 2 diabetes are critical to improving our understanding of DPN pathophysiology and developing novel treatment strategies. Some drugs may demonstrate their healing potential by regulating neuroinflammation. Palmitoylethanolamide (PEA) is a prototype ALIAmide well‐known for its analgesic, anti‐inflammatory, and neuroprotective properties in several experimental models of neuroinflammation.Based on these findings, the aim of this work was to better examine the neuroprotective effects of a formulation of micronized PEA (PEA‐m) in a mouse model of DPN induced by streptozotocin injection. Diabetic and control animals received PEA‐m (10mg/kg) by oral gavage daily starting 2 weeks from streptozotocin injection. At 16 weeks, the animals were sacrificed and plasma, urine and sciatic nerve tissues were collected.Our results demonstrated that after diabetes induction, PEA‐m was able to reduce mechanical and thermal hyperalgesia and motor alterations as well as reduced mast cells activation and NGF expression. In addition, PEA‐m decreased neural histological damage, oxidative and nitrosative stress, citokines release, angiogenesis and apoptosis maybe by modulating inflammatory pathways such as nuclear NF‐κB or MAP kinases.In conclusion, we demonstrated that PEA‐m could represent a new therapeutic strategy to combat neuroinflammation and pain associated to diabetic neuropathy.Support or Funding InformationNo funding was providedThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fluorescence-Based Analysis of Noncanonical Functions of Aminoacyl-tRNA Synthetase-Interacting Multifunctional Proteins (AIMPs) in Peripheral Nerves.

Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) are auxiliary factors involved in protein synthesis related to aminoacyl-tRNA synthetases (ARSs). AIMPs, which are well known as nonenzymatic factors, include AIMP1/p43, AIMP2/p38, and AIMP3/p18. The canonical functions of AIMPs include not only protein synthesis via multisynthetase complexes but also maintenance of the structural stability of these complexes. Several recent studies have demonstrated nontypical (noncanonical) functions of AIMPs, such as roles in apoptosis, inflammatory processes, DNA repair, and so on. However, these noncanonical functions of AIMPs have not been studied in peripheral nerves related to motor and sensory functions. Peripheral nerves include two types of structures: peripheral axons and Schwann cells. The myelin sheath formed by Schwann cells produces saltatory conduction, and these rapid electrical signals control motor and sensory functioning in the service of survival in mammals. Schwann cells play roles not only in myelin sheath formation but also as modulators of nerve degeneration and regeneration. Therefore, it is important to identify the main functions of Schwann cells in peripheral nerves. Here, using immunofluorescence technique, we demonstrated that AIMPs are essential morphological indicators of peripheral nerve degeneration, and their actions are limited to peripheral nerves and not the dorsal root ganglion and the ventral horn of the spinal cord.

The histone deacetylase class I, II inhibitor trichostatin A delays peripheral neurodegeneration.

Peripheral nerves, which consist of an axon and a unique glial cell called a Schwann cell, transduce signals from the brain and spinal cord to target organs. Peripheral nerve degeneration leads to distal motor or sensory disorders such as diabetic neuropathy, Charcot-Marie-Tooth disease, and Gullain-Barré syndrome, with symptoms such as dysesthesia, speech impairment, vision change, erectile dysfunction, and urinary incontinence. Schwann cells play an important role in peripheral nerve degeneration. Therefore, revealing the characteristics of Schwann cells will be essential in understanding peripheral neurodegeneration-related diseases for which there is currently no effective treatment. Trichostatin A (TSA) is a noncompetitive, reversible inhibitor of class I and II histone deacetylases (HDACs). HDACs have been shown not only to deacetylate histones but also to target non-histone proteins involved in diverse signaling pathways. Recent studies have revealed that diverse HDAC subtypes regulate peripheral neurodegeneration. Thus, regulating HDAC levels could be an effective strategy for the development of drugs targeting peripheral nerve-related diseases. In fact, the use of TSA has been investigated for the treatment of many diseases, including degenerative diseases of the central nervous system; however, the effects of TSA on peripheral neurodegeneration have not yet been well established. In this study, we revealed the effect of TSA on the process of peripheral neurodegeneration. TSA successfully inhibited myelin fragmentation, axonal degradation, and trans-dedifferentiation and proliferation of Schwann cells, which are essential phenotypes in peripheral neurodegeneration. Therefore, TSA could be a potential drug for patients suffering from peripheral neurodegeneration-related diseases.

The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice

ABSTRACTIntroduction: Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load.Methods: Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months.Results: We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice.Discussion: Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed.Abbreviations: CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization

MiR-34c Participates in Diabetic Corneal Neuropathy Via Regulation of Autophagy.

To investigate the contribution and mechanism of miRNAs and autophagy in diabetic peripheral neuropathy. In this study, we used streptozotocin (STZ)-induced type I diabetes C57 mice as animal models, and we detected the expression of miR-34c and autophagic intensity in trigeminal ganglion (TG) tissue. The bioinformatics software was used to predict and analyze the potential targets of miR-34c. Primary trigeminal ganglion neurons were cultured in vitro to investigate the effect of miR-34c on axon growth and survival of TG cells. A corneal epithelial damage-healing model was established on the diabetic mice, then miR-34c antagomir was injected subconjunctivally. The condition of corneal epithelial healing was observed through sodium fluorescein staining, and the peripheral nerve degeneration of the cornea was evaluated by β-tublin corneal nerve staining. The expression of miR-34c was significantly increased in TG tissue of type I diabetic mice by real-time PCR. Western blot showed that autophagy-related proteins Atg4B and LC3-II were significantly down-regulated in diabetes TG compared with normal control. Trigeminal neuron immunofluorescence showed that the length of the trigeminal ganglion cell synapses was significantly increased after miR-34c antagomir treatment compared with normal cultures. Subconjunctival injection of miR-34c antagomir can significantly promote corneal epithelium healing of diabetic mice and appreciably promote the regeneration of corneal nerve. At the same time, it can significantly increase the expression of autophagy in TG tissue of type I diabetic mice. In this study , miR-34c was found to affect the growth of trigeminal sensory neurons and the repair of diabetic corneal nerve endings by acting directly on Atg4B.

Comparative study of microarray and experimental data on Schwann cells in peripheral nerve degeneration and regeneration: big data analysis.

A Schwann cell has regenerative capabilities and is an important cell in the peripheral nervous system. This microarray study is part of a bioinformatics study that focuses mainly on Schwann cells. Microarray data provide information on differences between microarray-based and experiment-based gene expression analyses. According to microarray data, several genes exhibit increased expression (fold change) but they are weakly expressed in experimental studies (based on morphology, protein and mRNA levels). In contrast, some genes are weakly expressed in microarray data and highly expressed in experimental studies; such genes may represent future target genes in Schwann cell studies. These studies allow us to learn about additional genes that could be used to achieve targeted results from experimental studies. In the current big data study by retrieving more than 5000 scientific articles from PubMed or NCBI, Google Scholar, and Google, 1016 (up- and downregulated) genes were determined to be related to Schwann cells. However, no experiment was performed in the laboratory; rather, the present study is part of a big data analysis. Our study will contribute to our understanding of Schwann cell biology by aiding in the identification of genes. Based on a comparative analysis of all microarray data, we conclude that the microarray could be a good tool for predicting the expression and intensity of different genes of interest in actual experiments.

Regulatory Mechanism of Peripheral Nerve Myelination by Glutamate-Induced Signaling.

Regulation of differentiation and proliferation of Schwann cells is an essential part of the regulation of peripheral nerve development, degeneration, and regeneration. ZNRF1, a ubiquitin ligase, is expressed in undifferentiated/repair Schwann cells, directs glutamine synthetase to proteasomal degradation, and thereby increase glutamate levels in Schwann cell environment. Glutamate elicits subcellular signaling in Schwann cells via mGluR2 to modulate Neuregulin-1/ErbB2/3 signaling and thereby promote undifferentiated phenotype of Schwann cell.

Hyperbaric oxygen therapy in peroneal nerve damage due to lithotomy position

Peripheral neuropathies can be seen in patients who are operated in lithotomy position. In this case report, patient which had right drop foot after urethroplasty surgery in lithotomy position was treated. Electromyography (EMG) was performed at postoperative 1st day and demonstrated right peroneal nerve palsy. Physiotherapy (knee extension, cycling, and passive dorsiflexion), vitamin B complex (B1, B6, folic acid and B12) and daily hyperbaric oxygen treatment were started. Fifth day after surgery, improvement of moving the right foot was detected clinically. Patient was discharged on 7th postoperative day and neurologist suggested to continue physiotherapy and vitamin B complex for 3 weeks. After this period, control EMG showed the development of peroneal nerve functions. The patient had a fully functional right foot with all these treatments one month after surgery. Effectivity of hyperbaric oxygen in treatment of peripheral nerve degeneration was seen in several studies in literature (4). In a few studies, the effect of hyperbaric oxygen on peroneal nerve palsy has not been demonstrated (5). The patient recovered earlier than other patients in literature. In this case, the treatment difference was hyperbaric oxygen treatment from other cases in literature. Before the start of lithotomy operations, patients should be carefully evaluated for peroneal nerve palsy risk factors and appropriately positioned to prevent iatrogenic peroneal nerve palsy in the operation. After operation, if peroneal nerve palsy develops, physiotherapy should start as soon as possible. Hyperbaric oxygen is kept in mind as supplemental treatment even if it is not in standard treatment protocol in peroneal nerve palsy.

Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

The Effect of Vascular Graft and Human Umbilical Cord Blood-Derived CD34+ Stem Cell on Peripheral Nerve Healing.

AIM:There are many trials concerning peripheral nerve damage causes and treatment options. Unfortunately, nerve damage is still a major problem regarding health, social and economic issues. On this study, we used vascular graft and human cord blood derived stem cells to find an alternative treatment solution to this problem.MATERIAL AND METHODS:We used 21 female Wistar rats on our study. They were anesthetized with ketamine and we studied right hind limbs. On Group 1, we did a full layer cut on the right sciatic nerve. On Group 2, we did a full layer cut on the right sciatic nerve, and we covered synthetic vascular graft on cut area. On Group 3, we did a full layer cut on right sciatic nerve, and we covered the area with stem cell applied vascular graft.RESULTS:At the end of postoperative 8. weeks, we performed EMG on the rats. When we compared healthy and degenerated areas as a result of EMG, we found significant amplitude differences between the groups on healthy areas whereas there was no significant difference on degenerated areas between the groups. Then we re-opened the operated area again to reveal the sciatic nerve cut area, and we performed electron microscope evaluation. On the stem cell group, we observed that both the axon and the myelin sheet prevented degeneration.CONCLUSION:This study is a first on using synthetic vascular graft and cord blood derived CD34+ cells in peripheral nerve degeneration. On the tissues that were examined with electron microscope, we observed that CD34+ cells prevented both axonal and myelin sheath degeneration. Nerve tissue showed similar results to the control group, and the damage was minimal.

Toll-Like Receptor 4 (TLR4) Expression Affects Schwann Cell Behavior in vitro

Peripheral nerve injury can result in the decreased quality of life and bring us economic burden on society and individuals. Wallerian degeneration (WD) is critical for nerve degeneration and regeneration, but the mechanisms of WD are still elusive. Here, we report the effect of Toll-like receptor 4 (TLR4) on cultured Schwann cells (SCs) in vitro. The data showed that TLR4 expression was up-regulated after sciatic nerve injury of rat. TLR4 was expressed in cultured SCs. Enhanced or silenced expression of TLR4 affected SC proliferation, migration, apoptosis and relative gene expression. Furthermore, altered expression of TLR4 resulted in expression changes in c-Jun, ERK and catenin but not AKT and c-Fos pathways in SCs. These results suggested that TLR4 may be an important effective target in peripheral nerve degeneration and/or regeneration during WD in future investigations.

P38. Longitudinal sonographic alterations of the peripheral nerve structure in ALS

Background We aimed to examine whether there are time-dependent alterations of the upper limb peripheral nerves’ structure in amyotrophic lateral sclerosis (ALS) applying high-resolution sonography and calculating various gray-scale measures. Material and methods This analysis included 69 ALS patients (mean [SD] age 63.9 [10.4] years, 62% male) that underwent at least two sonographic follow-up exams (FUs) (2 FUs n = 69, 3 FUs n = 31, 4 FUs n = 20, 5 FUs n = 11, 6 FUs n = 8, 7 FUs n = 4) of various distal and proximal segments of the median and ulnar nerve. Cross-sectional nerve area (CSA) and distinct gray-scale measures comprising median echo intensity (EI), echo variance (EV), hypo echogenic fraction (HF) and textural correlation (TCOR) were calculated. Repeated-measures ANOVA was conducted contrasting the first against the last available sonographic exam and comprising timespan between those two measures as a covariate. P-values were deemed to be significant at ⩽0.05. For every variable the slope β was calculated giving the unit and direction of change with respect to the timespan (in months) between last and baseline sonographic exam. Results During a mean [SD] disease duration of 6.6 [8.1] months ALS patients displayed alterations of all sonographic markers affecting various nerve segments comprising CSA (median nerve upper arm [UA] F(1) = 6.3, p = 0.02, β = −0.005), EI (ulnar nerve wrist [WR] F(1) = 6.1, p = 0.02, β = 0.1), EV (median nerve forearm [FA]; F(1) = 4.0, p = 0.05, β = 0.5; ulnar nerve WR F(1) = 13.2, p = 0.001, β = 0.5), HF (ulnar nerve WR F(1) = 3.2, p = 0.083, β = 0.01 [trend]) and TCOR (median nerve UA F(1) = 7.7, p = 0.009, β = −0.01; ulnar nerve FA F(1) = 6.3, p = 0.02, β = −0.005; ulnar nerve WR F(1) = 4.6, p = 0.04, β = −0.01). Conclusion In ALS, sonographic measures displayed peripheral nerve atrophy, EI and EV increase together with TCOR loss over the course of disease especially affecting nerve segments predominantly containing motor branches such as the upper arm median nerve or the wrist ulnar nerve. Findings seem to reflect peripheral nerve degeneration in terms of myelinated fiber loss and fibrous texture increase in ALS.

Abstract 602: The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity

Abstract While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor for chemotherapy or delay treatment. Our laboratories have previously shown that nicotine, the prototypical nicotinic acetylcholine receptor (nAChR) agonist, can prevent and reverse paclitaxel-induced peripheral neuropathy without increasing lung tumor growth in mice. Our current studies have demonstrated that the α7 nAChR silent agonist R-47 may be a promising preventative and therapeutic treatment for CIPN as well. R-47 (10 mg/kg, p.o.) was administered to male C57BL/6J mice treated with paclitaxel (8 mg/kg, i.p., every other day for a total of four injections). Von Frey filament testing revealed that R-47 can both prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect can be inhibited by the α7 nAChR antagonist methyllycaconitine. In support of these findings, R-47 also prevents the reduction of intra-epidermal nerve fibers in the hind paws of paclitaxel-treated mice. In addition, α7 nAChR knockout mice exhibit a greater and sustained increase in mechanical allodynia after paclitaxel administration when compared to wild-type mice, suggesting the involvement of this receptor subtype in hindering CIPN development and/or maintenance. With regard to cancer, R-47 fails to increase A549 and H460 non-small cell lung cancer cell viability, colony formation, or proliferation alone, and does not interfere with paclitaxel-induced growth arrest, apoptosis, or DNA fragmentation. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These data suggest that the use of an α7 nAChR silent agonist may be a safe and efficacious approach for the prevention and treatment of CIPN. Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 602.

Fas Ligand Gene (Faslg) Plays an Important Role in Nerve Degeneration and Regeneration After Rat Sciatic Nerve Injury.

Wallerian degeneration (WD) is associated with changes in the expression levels of a large number of genes. However, the effects of these up- or down-regulated genes are poorly understood. We have reported some key factors that are differentially regulated during WD in our previous research. Here, we explored the roles of Fas ligand gene (Faslg) in WD after rat sciatic nerve injury. The data showed that Faslg was up-regulated in injured nerves. Expression changed of Faslg in Schwann cells (SCs) resulted in alterations in the release of related factors. Silencing or overexpression of Faslg affected SC proliferation, migration, and apoptosis through β-catenin, nuclear factor-κB (NF-κB), and caspase-3 pathways in vivo and in vitro. Our data suggest that Faslg is a key regulatory gene that affects nerve repair and regeneration in peripheral nerve injury. This study sheds new light on the effects of Faslg on peripheral nerve degeneration and/or regeneration.