Wallerian Degeneration Of Peripheral Nerve Research Articles

Critical signaling pathways during Wallerian degeneration of peripheral nerve.

Wallerian degeneration is a critical biological process that occurs in distal nerve stumps after nerve injury. To systematically investigate molecular changes underlying Wallerian degeneration, we used a rat sciatic nerve transection model to examine microarray analysis outcomes and investigate significantly involved Kyoto Enrichment of Genes and Genomes (KEGG) pathways in injured distal nerve stumps at 0, 0.5, 1, 6, 12, and 24 hours, 4 days, 1, 2, 3, and 4 weeks after peripheral nerve injury. Bioinformatic analysis showed that only one KEGG pathway (cytokine-cytokine receptor interaction) was significantly enriched at an early time point (1 hour post-sciatic nerve transection). At later time points, the number of enriched KEGG pathways initially increased and then decreased. Three KEGG pathways were studied in further detail: cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and axon guidance. Moreover, temporal expression patterns of representative differentially expressed genes in these KEGG pathways were validated by real time-polymerase chain reaction. Taken together, the above three signaling pathways are important after sciatic nerve injury, and may increase our understanding of the molecular mechanisms underlying Wallerian degeneration.

Hydrogen sulfide controls peripheral nerve degeneration and regeneration: a novel therapeutic strategy for peripheral demyelinating disorders or nerve degenerative diseases.

After peripheral nerve injury, the process of Wallerian degeneration is initiated in the distal stump of injured nerves. Wallerian degeneration in peripheral nerves involves axonal degeneration and degradation of the myelin sheath in Schwann cells. This provides the necessary conditions for axonal regeneration and remyelination. After nerve injury, macrophages are also recruited to the distal nerve stump and, together with Schwann cells, play a role in the clearance of myelin debris. Thus, a series of processes help to promote peripheral nerve regeneration, which includes axonal regeneration and remyelination. This is in contrast to injuries within the adult central nervous system, in which successful regeneration encounters several significant barriers: myelin-associated inhibition (Neuman et al., 2002), diminished axonal growth capacity (Ruff et al., 2008) and glial scarring (Yiu and He, 2006). Because the successful regeneration of injured peripheral nerves relies on a harmonious degenerating process, it is essential to identify a molecular mechanism that regulates axonal degeneration or myelin fragmentation during Wallerian degeneration to foster the conditions allowing efficient peripheral nerve regeneration. We have recently shown that hydrogen sulfide (H2S) is important for axonal degradation and demyelination. We focus here on the effects of H2S on axonal degradation and on understanding the underlying mechanisms of H2S-associated demyelination, dedifferentiation and proliferation in Schwann cells during Wallerian degeneration. In addition, we discuss a novel strategy for nerve regeneration in the injured perip heral nerve or peripheral neuropathy.

Local production of serum amyloid a is implicated in the induction of macrophage chemoattractants in Schwann cells during wallerian degeneration of peripheral nerves

The elevation of serum levels of serum amyloid A (SAA) has been regarded as an acute reactive response following inflammation and various types of injuries. SAA from the liver and extrahepatic tissues plays an immunomodulatory role in a variety of pathophysiological conditions. Inflammatory cytokines in the peripheral nerves have been implicated in the Wallerian degeneration of peripheral nerves after injury and in certain types of inflammatory neuropathies. In the present study, we found that a sciatic nerve axotomy could induce an increase of SAA1 and SAA3 mRNA expression in sciatic nerves. Immunohistochemical staining showed that Schwann cells are the primary sources of SAA production after nerve injury. In addition, interleukin-6-null mice, but not tumor necrosis factor-α-null mice showed a defect in the production of SAA1 in sciatic nerve following injury. Dexamethasone treatment enhanced the expression and secretion of SAA1 and SAA3 in sciatic nerve explants cultures, suggesting that interleukin-6 and corticosteroids might be major regulators for SAA production in Schwann cells following injury. Moreover, the stimulation of Schwann cells with SAA1 elicited the production of the macrophage chemoattractants, Ccl2 and Ccl3, in part through a G-protein coupled receptor. Our findings suggest that locally produced SAA might play an important role in Wallerian degeneration after peripheral nerve injury.

Anatomic basis for denervation of the spermatic cord for chronic orchialgia: trifecta of pain

OBJECTIVE: Levine et al. have shown that microsurgical denervation of the spermatic cord (MDSC) is a treatment option for men with chronic orchialgia (CO). Uceyler et al. have shown that patients with neuropathic pain may have Wallerian degeneration in peripheral nerves. This study provides an anatomical basis on how the denervation technique may provide pain relief.

Over‐expression of alpha‐synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion in a transgenic mouse strain

Wallerian degeneration in peripheral nerves occurs after a traumatic insult when the distal nerve part degenerates while peripheral macrophages enter the nerve stump and remove the accruing debris by phagozytosis. We used an experimental model to investigate the effect of either the absence or over-expression of alpha-synuclein (alpha-syn) after transecting the sciatic nerves of mice. alpha-Synuclein is a major component of Lewy bodies and its aggregation results in a premature destruction of nerve cells. It has also been found present in different peripheral nerves but its role in the axon remains still unclear. Following sciatic nerve transection in different mouse strains, we investigated the numbers of invading macrophages, the amounts of remaining myelin and axons 6 days after injury. All mice showed clear signs of Wallerian degeneration, but transgenic mice expressing human wild-type alpha-syn showed lower numbers of invading macrophages, less preserved myelin and significantly lower numbers of preserved axons in comparison with either knockout mice or a mouse strain with a spontaneous deletion of alpha-syn. The use of protein aggregation filtration blots and paraffin-embedded tissue blots displayed depositions of alpha-syn aggregates within sciatic nerve axons of transgenic mice. Thicker myelin sheaths and higher numbers of mitochondria were detected in old alpha-syn transgenic mice. In a human sural nerve, alpha-syn could also be identified within axons. Thus, alpha-syn and its aggregates are not only a component of Lewy bodies and synapses but also of axons and these aggregates might interfere with axonal transport. alpha-Synuclein transgenic mice represent an appropriate model for investigations on axonal transport in neurodegenerative diseases.

1880 TRIFECTA OF PAIN: ANATOMIC BASIS FOR DENERVATION OF THE SPERMATIC CORD FOR CHRONIC ORCHIALGIA

You have accessJournal of UrologyInfertility: Physiology, Pathophysiology, Basic Research1 Apr 20101880 TRIFECTA OF PAIN: ANATOMIC BASIS FOR DENERVATION OF THE SPERMATIC CORD FOR CHRONIC ORCHIALGIA Sijo Parekattil, Karen Priola, Hany Atalah, Marc Cohen, Johannes Vieweg, and Robert Allen Sijo ParekattilSijo Parekattil More articles by this author , Karen PriolaKaren Priola More articles by this author , Hany AtalahHany Atalah More articles by this author , Marc CohenMarc Cohen More articles by this author , Johannes ViewegJohannes Vieweg More articles by this author , and Robert AllenRobert Allen More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1833AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Levine et al. have shown that microsurgical denervation of the spermatic cord is a treatment option for men with chronic orchialgia (CO). Uceyler et al. have shown that patients with neuropathic pain may have Wallerian degeneration in peripheral nerves. This study was aimed at developing an anatomical basis of how the denervation technique may provide pain relief. METHODS A prospective control study was performed. Specimens of tissue transected in a standardized fashion from cross-sections of the spermatic cord during 30 microsurgical denervation procedures and 4 varicocelectomies performed (May to Oct 2009) by a single microsurgeon (SJP) were reviewed. All specimens were reviewed by a single pathologist (RWA), blinded to the tabulated results of total number of nerves, size and any evidence of pathology (hematoxylin-eosin staining). All denervation cases were performed in men with CO that had failed conservative treatment options (negative urologic and neurologic workup). The 4 varicocelectomy cases were the control group (no CO). A human cadaver dissection was performed to confirm localization of the nerve distribution found on pathology. RESULTS There were an average of 20 reproducible small diameter (<1 mm) nerve fibers within the spermatic cord per patient. 83% (25/30) of orchialgia patients were found to have Wallerian degeneration in at least one or more of these nerves. Only 25% (1/4) patients had Wallerian degeneration in the varicocelectomy group. There was a characteristic distribution of nerves within the cord. There were 3 primary locations, listed in decreasing order of nerve density: 1) Cremasteric muscle fibers (8 nerves/patient), 2) Peri-vasal tissues and vasal sheath (7.6 nerves/patient), and 3) Peri-arterial tissues (1.9 nerves/patient). The nerve distribution was anatomically confirmed on the cadaver dissection. CONCLUSIONS There is an anatomical basis to the success of microsurgical denervation of the spermatic cord for men with chronic orchialgia. There appear to be specific distribution patterns of small diameter nerve fibers within the spermatic cord. There appears to be a significant amount of Wallerian degeneration in spermatic cord nerve fibers in men with chronic orchialgia. This study confirms the key components of the denervation procedure: 1) ligation of cremasteric fibers, 2) ligation of the peri-vasal sheath, and 3) ligation of the peri-arterial tissues. The transsection of these nerves may explain the effect of the denervation procedure. Gainesville, FL© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byLarsen S, Benson J and Levine L (2012) Microdenervation of the Spermatic Cord for Chronic Scrotal Content Pain: Single Institution Review Analyzing Success Rate After Prior Attempts at Surgical CorrectionJournal of Urology, VOL. 189, NO. 2, (554-558), Online publication date: 1-Feb-2013. Volume 183Issue 4SApril 2010Page: e730-e731 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sijo Parekattil More articles by this author Karen Priola More articles by this author Hany Atalah More articles by this author Marc Cohen More articles by this author Johannes Vieweg More articles by this author Robert Allen More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Nature of signals that initiate the immune response during Wallerian degeneration of peripheral nerves

Monocyte chemoattractant protein-1 is produced by Schwann cells during Wallerian degeneration of a peripheral nerve and contributes to a selective accumulation of macrophages in the degenerating segment. An in vitro preparation has been developed to analyze the molecules from axons and non-neuronal cells in nerves that stimulate an increased production of monocyte chemoattractant protein-1 mRNA by Schwann cells. For this purpose, Schwann cells obtained from neonatal rats were maintained in culture, exposed to putative molecular stimuli and analyzed for their content of monocyte chemoattractant protein-1 mRNA. Under basal conditions, the concentration of monocyte chemoattractant protein-1 in Schwann cells was low. Freeze-killed fragments or homogenates of nerve (or brain) but not viable nerve or freeze-killed muscle were effective in inducing monocyte chemoattractant protein-1 mRNA. The inductive activity was abolished by heating. Results of dialysis of supernatants of nerve homogenates indicate that a protein or proteins of 1–10 kDa were capable of stimulating synthesis of monocyte chemoattractant protein-1 by Schwann cells. Also, the activity in nerve homogenates was partially inhibited by antibodies to Toll-like receptor-4. The observations suggest that a non-secreted protein is released from disintegrating axons to initiate the innate immune response that characterizes Wallerian degeneration.

Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1 and interleukin-1 in Wallerian degeneration

Wallerian degeneration in the CNS and PNS consists of degradation and phagocytosis of axons and their myelin sheath distal to the site of injury. This process of degeneration, which requires an effective macrophage response, occurs rapidly in peripheral nerves but is slow in the CNS. Rapid Wallerian degeneration in peripheral nerves may contribute to subsequent axonal regeneration. We show that there is a marked increase in mRNA expression of three pro-inflammatory molecules, the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), and the cytokine interleukin-1beta (IL-1beta), in the mouse sciatic nerve but not in the spinal cord undergoing Wallerian degeneration. Neutralizing MCP-1, MIP-1alpha and IL-1beta in the lesioned sciatic nerve with function-blocking antibodies suppressed macrophage responses and myelin clearance. Injecting recombinant MCP-1, MIP-1alpha or IL-1beta into the normal, uninjured spinal cord triggered the expression of a number of chemokines and cytokines. Furthermore, injecting recombinant MCP-1/MIP-1alpha or IL-1beta into the dorsal column of the spinal cord undergoing Wallerian degeneration triggered rapid macrophage/microglial activation and myelin clearance. These findings provide direct evidence that MCP-1, MIP-1alpha and IL-1beta are important regulators of macrophage responses that lead to rapid myelin breakdown and clearance in Wallerian degeneration.

Blocking of up-regulated ICAM-1 does not prevent macrophage infiltration during Wallerian degeneration of peripheral nerve

Circulating blood monocytes infiltrate into distal degenerating nerve and differentiate into activated macrophages that remove degenerating axonal and myelin debris and promote axonal regeneration. The cellular and molecular mechanisms responsible for this monocyte–macrophage recruitment remain largely unknown. Cell adhesion molecules which mediate monocyte and endothelial cell interactions, such as the endothelial cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) interaction with the monocyte adhesion molecules Mac-1 (complement receptor type 3) and LFA-1 (lymphocyte function-associated antigen-1), have been shown to play a critical role in mediating the transendothelial migration of circulating monocytes into nonneural tissues following various types of injury. This study investigated whether these cell adhesion molecules also play a critical role in mediating monocyte–macrophage infiltration during Wallerian degeneration of peripheral nerve. Following sciatic nerve transection, Mac-1- and LFA-1-positive macrophages in distal degenerating nerve increased in number at 2 days and peaked at 14 days before declining. The number of ICAM-1-immunostained blood vessels increased maximally at 1 day before declining to baseline levels by 14 days. Three days following nerve transection, the intensity of ICAM-1 immunostaining on intraneural blood vessels was maximal and then decreased to baseline levels by 14 days. To test the role of ICAM-1 in mediating monocyte–macrophage recruitment, we used two complementary experimental strategies following a sciatic nerve transection: (1) intravenous administration of a rat ICAM-1-blocking monoclonal antibody and (2) ICAM-1 knockout mice. In both cases, the number of infiltrating monocytes–macrophages was above controls, which is opposite to what has been shown to occur in other tissues following injury.

Phospholipase A2 plays an important role in myelin breakdown and phagocytosis during wallerian degeneration

Phospholipase A2 (PLA2) hydrolyzes phosphatidylcholine to lysophosphatidylcholine and arachidonic acid. The former can induce myelin breakdown and the latter, via eicosanoids, can stimulate inflammatory responses. Immunohistochemical analysis of secreted (sPLA2) and cytosolic (cPLA2) forms of the enzyme was assessed in the injured adult rat sciatic and optic nerves. sPLA2 and cPLA2 are expressed in the first 2 weeks in the injured sciatic nerve, which correlates with rapid Wallerian degeneration in peripheral nerves. In contrast, both forms of PLA2 were not expressed in the optic nerve for the first 3 weeks after crush injury, which correlates with slow Wallerian degeneration in the central nervous system (CNS). In addition, PLA2 is not expressed in the lesioned sciatic nerve of C57BL/Wlds mutant mice in which Wallerian degeneration is severely retarded. Blocking cPLA2 in the transected sciatic nerve of C57BL/6 mice, which have a naturally occurring null mutation for the major from of sPLA2, resulted in a marked slowing of myelin and axonal degradation and phagocytosis in the distal nerve segment. These results provide direct evidence of an important role for cPLA2 in Wallerian degeneration.

Complement Depletion Reduces Macrophage Infiltration and Activation during Wallerian Degeneration and Axonal Regeneration

After peripheral nerve injury, macrophages infiltrate the degenerating nerve and participate in the removal of myelin and axonal debris, in Schwann cell proliferation, and in axonal regeneration. In vitro studies have demonstrated the role serum complement plays in both macrophage invasion and activation during Wallerian degeneration of peripheral nerve. To determine its role in vivo, we depleted serum complement for 1 week in adult Lewis rats, using intravenously administered cobra venom factor. At 1 d after complement depletion the right sciatic nerve was crushed, and the animals were sacrificed 4 and 7 d later. Macrophage identification with ED-1 and CD11a monoclonal antibodies revealed a significant reduction in their recruitment into distal degenerating nerve in complement-depleted animals. Complement depletion also decreased macrophage activation, as indicated by their failure to become large and multivacuolated and their reduced capacity to clear myelin, which was evident at both light and electron microscopic levels. Axonal regeneration was delayed in complement-depleted animals. These findings support a role for serum complement in both the recruitment and activation of macrophages during peripheral nerve degeneration as well as a role for macrophages in promoting axonal regeneration.

Changes in water diffusion due to Wallerian degeneration in peripheral nerve.

The authors report NMR measurements of the changes in water diffusion brought about by in vivo Wallerian degeneration due to either crush- or tie-injuries in the sciatic nerve of the frog. Using a pulsed-gradient spin-echo sequence with a diffusion measurement time of 28 ms, the degree of diffusion coefficient anisotropy ¿D(longitudinal)/D(transverse)¿ 4 weeks after injury in both crush- and tie-injured nerves (2.3 +/- 0.4 and 1.7 +/- 0.1, respectively) is significantly less than in normal frog sciatic nerve (3.9 +/- 0.4). The decrease of anisotropy in the degenerated nerves is due to both a decrease in longitudinal diffusion and an increase in transverse diffusion. The changes in diffusion coefficients are compared with the degree of axonal and myelin breakdown observed in light and electron micrographs of the nerves.

Mechanisms of macrophage recruitment in Wallerian degeneration.

Monocytes/macrophages are important effector cells in myelin removal during Wallerian degeneration. Experiments with the mouse mutant C57BL/Ola revealed prolonged axonal survival and reduced phagocytic cell recruitment after nerve transsection. In the present study, we compared the course of Wallerian degeneration in peripheral nerves of C57BL and C57BL/Ola mice in vivo and in vitro. In vivo experiments confirmed earlier investigations describing a delayed degeneration in the C57BL/Ola mutant compared with C57BL mice which were used as control animals without abnormal degeneration. Quite different results were seen in experiments in vitro: degenerating nerve segments of C57BL/Ola mice revealed pronounced axonal breakdown even in the absence of non-resident phagocytic cells. There was no difference in vitro compared with degenerating nerves from C57BL mice. The differences observed between the in vivo and in vitro situations suggest that axonal breakdown plays an important role in the initiation of macrophage recruitment to degenerating peripheral nerves.

The β2-adrenergic agonist terbutaline suppresses experimental allergic neuritis in Lewis rats

Treatment of rats with experimental allergic neuritis with the β 2-adrenergic agonist terbutaline suppresses clinical symptoms, decreases demyelination and Wallerian degeneration in peripheral nerves and improves electrophysiological parameters. Treatment is highly effective when given from the time of immunization through the acute phase of illness, when given for the first 12 days after immunization and also when given after the onset of the disease.

Anti-macrophage CR3 antibody blocks myelin phagocytosis by macrophages in vitro

Myelin phagocytosis in Wallerian degeneration of peripheral nerves depends on invasion of nerves by non-resident macrophages. The present study was done to clarify the role of the macrophage complement receptor type 3 (CR3) in myelin removal. Myelin phagocytic capacity of invading macrophages was abolished by treatment of cultured nerves and macrophages with anti-CR3 antibody or by serum complement depletion with cobra venom factor. This indicates that myelin phagocytosis is mediated by the macrophage CR3.

Organic arsenic‐induced Guillain‐Barré‐like syndrome due to melarsoprol: A clinical, electrophysiological, and pathological study

A young woman suffering from sleeping sickness was treated with melarsoprol. Thirty-eight days after the first administration of this organo-arsenic compound, myalgias, distal paresthesias and rapidly progressive weakness developed in all four limbs. Electrophysiological studies were misleading for Guillain-Barré syndrome. Neuropathological data included massive distal wallerian degeneration in peripheral nerves and abnormalities in dorsal ganglia and spinal cord where vacuolation of anterior horn cells and axonal neurofilamentous masses were observed. Very high concentrations of arsenic were found in the spinal cord, contrasting with undetectable levels in peripheral nerves. Our findings are consistent with an arsenic neuronopathy manifested by initial proximal demyelination and delayed distal axonal damage. Renal and hepatic dysfunctions, which were implicated in the toxic arsenic accumulation, should be systematically detected before administration of melarsoprol. The diagnosis of Guillain-Barré syndrome must be considered with caution in patients treated with this compound.

Myelin phagocytosis in Wallerian degeneration of peripheral nerves depends on silica-sensitive, bg/bg-negative and Fc-positive monocytes.

Previous experiments with nerves enclosed in millipore diffusion chambers had shown that myelin degradation during Wallerian degeneration depends on invasion by non-resident cells. The present study was aimed at a more precise identification of the invading cell population. Monoclonal antibody studies of degenerating nerves showed many cells with the Fc marker; cells having the Lyt-1, Lyt-2, Ia or Mac-1 markers were sparse or absent. Nerves transplanted into mice of the Chediak-Higashi bg/bg strain were invaded by cells lacking the bg/bg marker (giant lysosomes), while cotransplanted muscle tissue was invaded by cells with the bg/bg marker. Blocking monocytes with silica reduced both cell invasion and myelin degradation in degenerating nerves. These observations show that Wallerian degeneration of peripheral nerve fibers involves a subset of monocytes which are silica-sensitive and have Fc receptors but no bg/bg giant lysosomes.

Wallerian degeneration of peripheral nerve. Age-dependent loss of nerve lipids.

The age-dependent loss of the major peripheral nerve lipids (cholesterol, phospholipid, and total galactolipid) was quantitated over a period of 9 weeks of Wallerian degeneration induced by surgical transection of rabbit sciatic nerves in animals of several ages. Proportionate losses of these lipids were determined by calculating the content of each lipid on a per nerve and on a per gram fresh weight basis remaining after a given period of Wallerian degeneration as a percent of original normal values at several time following surgery. The proportionate loss of each lipid from the distal stump was the most prompt and the most complete in nerves transected at 2 weeks of age, and the least in nerves transected at 20 weeks of age. The prompter clearance of these lipids from younger than older degenerating nerve gives convincing evidence that the suggestion from light-microscopic studies of faster clearance of neural debris in younger than in older animals is correct. A possible relationship between these biochemical findings and the phenomenon of greater functional recovery from peripheral nerve injury in younger than in older subjects is discussed.

Origin of macrophages in traumatic lesions and Wallerian degeneration in peripheral nerves.

The origin of the macrophages in peripheral nerves was investigated in newborn rabbits after labelling the blood monocytes with intravenous carbon suspensions.

Histochemistry of myelin. XI. Loss of basic protein in early myelin breakdown and multiple sclerosis plaques.

the early stages of Wallerian degeneration in peripheral nerves are accompanied by loss of a trypanophilic, trypsin-digestible basic protein from myelin. This loss of basic protein is ascribed to the activity of proteolytic enzymes. The reduced trypanophilia in degenerating nerves could not be attributed to loss of lipid. Likewise, the tryptophan-rich trypsin-resistant neurokeratin component of peripheral nerve myelin showed no change in the first week of degeneration. Loss of basic protein has been observed in and surrounding plaques of multiple sclerosis. We infer that digestion of basic protein would lead to the release of the encephalitogenic antigen contained therein.