Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria.

INTRODUCTION: A 24-year-old man with primary hyperoxaluria type 1 (PH1) presented with a rapidly progressive axonal and demyelinating sensorimotor polyradiculoneuropathy shortly after the onset of end-stage renal disease. His plasma oxalate level was markedly elevated at 107 µmol/L (normal<1.8 µmol/L). METHODS: A sural nerve biopsy was performed. Teased fiber and paraffin and epoxy sections were done and morphometric procedures were performed on this sample and on an archived sample from a 22-year-old man as an age- and gender-matched control. Embedded teased fiber electron microscopy was also performed. RESULTS: The biopsy revealed secondary demyelination and axonal degeneration. Under polarized light, multiple bright hexagonal, rectangular, and starburst inclusions, typical of calcium oxalate monohydrate crystals, were seen. CONCLUSIONS: The proposed mechanisms of nerve damage include disruption of axonal transport due to crystal deposition, toxic effect of oxalate, or nerve ischemia related to vessel occlusion from oxalate crystal deposition.

Oxaliplatin induces hypomyelination and reduced neuregulin 1 expression in the rat sciatic nerve.

Oxaliplatin causes severe peripheral neuropathy. In this study, we examined hypomyelination in the peripheral nerve in oxaliplatin-induced neuropathy rat model. Gene expression of neuregulin 1 (NRG1), a myelination regulatory factor, is reduced in the dorsal root ganglion (DRG) in DNA microarray analysis. Oxaliplatin increased the g-ratio and reduced levels of myelin protein zero in sciatic nerve, suggesting the hypomyelination. Moreover, oxaliplatin reduced NRG1 mRNA levels in the DRG and decreased levels of cleaved NRG1 type III protein in the sciatic nerve. Our results indicate that oxaliplatin induces hypomyelination and reduced NRG1 expression.

Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease.

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (postdisease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.

TACE (ADAM17) inhibits Schwann cell myelination.

Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

[Correlation and toxicological significance between myelin protein zero and peripheral nerve disease].

Myelin protein zero (P0) is the major structural element of peripheral myelin that plays a very important role in maintaining the stability of myelin. Recently, many researches find that the structure, distribution and function of P0 have transcended people's early understanding. In this review, the basic features of structure, distribution and function of P0 and its current research advances in neurotoxicology are simply summarized.

Distribution of Foxp3(+) T-regulatory cells in experimental autoimmune neuritis rats.

T-regulatory cells expressing the forkhead box transcription factor 3 (Foxp3) play essential roles in immune homeostasis. Experimental autoimmune neuritis (EAN) is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. We investigated the distribution of Foxp3(+) cells in sciatic nerves, spleen and lymph nodes of EAN rats, and the influence of FTY720 on the localization of Foxp3(+) cells in EAN rats. In sciatic nerves of EAN rats, accumulation of Foxp3(+) cells was not seen during the pre-symptomatic phase (until Day 9) or during early or peak disease activity. In contrast, Foxp3(+) cell accumulation was regularly seen in the recovery from neurologic disease, suggesting a contribution of Foxp3(+) cells to the resolution of EAN. FTY720 was given at onset of EAN (Day 10) until Day 18. Following FTY720 administration, percentages of Foxp3(+) cells in EAN rats were increased in circulating blood, but reduced in lymph nodes compared to the PBS control. FTY720 treatment suppressed total numbers but increased percentages of Foxp3(+) cells in sciatic nerves of EAN rats. These data not only suggests a protective role of Foxp3(+) cells in EAN but also provides a potential way to alter localization of Foxp3(+) cells in vivo.

Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers.

Paranodal axo-glial junctions are important for ion channel clustering and rapid action potential propagation in myelinated nerve fibers. Paranode formation depends on the cell adhesion molecules neurofascin (NF) 155 in glia, and a Caspr and contactin heterodimer in axons. We found that antibody to ganglioside GM1 labels paranodal regions. Autoantibodies to the gangliosides GM1 and GD1a are thought to disrupt nodes of Ranvier in peripheral motor nerves and cause Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To elucidate ganglioside function at and near nodes of Ranvier, we examined nodes in mice lacking gangliosides including GM1 and GD1a. In both peripheral and central nervous systems, some paranodal loops failed to attach to the axolemma, and immunostaining of Caspr and NF155 was attenuated. K(+) channels at juxtaparanodes were mislocalized to paranodes, and nodal Na(+) channel clusters were broadened. Abnormal immunostaining at paranodes became more prominent with age. Moreover, the defects were more prevalent in ventral than dorsal roots, and less frequent in mutant mice lacking the b-series gangliosides but with excess GM1 and GD1a. Electrophysiological studies revealed nerve conduction slowing and reduced nodal Na(+) current in mutant peripheral motor nerves. The amounts of Caspr and NF155 in low density, detergent insoluble membrane fractions were reduced in mutant brains. These results indicate that gangliosides are lipid raft components that contribute to stability and maintenance of neuron-glia interactions at paranodes.

Expression of CD28-related costimulatory molecule and its ligand in inflammatory neuropathies.

BACKGROUND: Activation of effector T lymphocytes, mediated in part by costimulatory molecules, is an important mechanism in the pathogenesis of immune-mediated diseases of the peripheral nervous system (PNS). OBJECTIVE: To analyze the expression and distribution pattern of the inducible costimulator (ICOS), a recently identified costimulatory molecule implicated in T-cell activation, and its unique ligand (ICOS-L), in inflammatory disorders of the PNS. METHODS: We studied RNA and protein expression in sural nerve biopsy specimens from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and vasculitic neuropathy (VN) vs patients with hereditary neuropathies (HNs) serving as a noninflammatory control using reverse-transcriptase PCR and immunohistochemistry. In addition, in vitro analysis was performed by flow cytometry. RESULTS: ICOS and ICOS-L mRNA was found to be significantly upregulated in samples from patients with GBS, CIDP, and VN compared to HNs. Immunohistochemistry identified T lymphocytes as the cellular source of ICOS, whereas macrophages expressed the corresponding ligand ICOS-L. Further analysis revealed that the distribution of ICOS-expressing T cells did not differ between acute and chronic inflamed PNS diseases. Correspondingly, the expression pattern of ICOS-L was similar in the inflamed tissues but differed significantly when compared to HNs. CONCLUSIONS: Inducible costimulator, expressed by T lymphocytes, and inducible costimulator ligand, expressed by macrophages within the peripheral nerve, might not only be relevant in inducing an acute immune response but might also be critically involved in perpetuating inflammation in chronically immune-mediated disorders of the peripheral nervous system.

Macrophage colony stimulating factor is a crucial factor for the intrinsic macrophage response in mice heterozygously deficient for the myelin protein P0.

Mouse mutants heterozygously deficient for the myelin protein P0 (P0+/-) resemble certain forms of human hereditary neuropathies. Endoneurial macrophages of intrinsic origin are intimately involved in the pathogenesis of the demyelinating neuropathy in these mutants. We have previously shown that deficiency for macrophage colony stimulating factor (M-CSF) prevents an increase of the number of endoneurial macrophages and alleviates the mutants' demyelinating phenotype. The aim of this study was to investigate which population of endoneurial macrophages - long-term resident macrophages or recently infiltrated macrophages - is affected by M-CSF deficiency. For this purpose, we generated bone marrow chimeric mice by transplanting GFP+ bone marrow into P0 mutants (P0+/-) and P0 mutants that lack M-CSF (P0+/- mcsf-op). This enabled us to discriminate recently infiltrated short-term resident GFP+ macrophages from long-term resident GFP- macrophages. Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice. In contrast, in P0+/- mcsf-op mutants, both GFP- and GFP+ macrophages did not substantially increase. Only small numbers of GFP+ but no GFP- macrophages were activated and phagocytosed myelin in chimeric P0+/- mcsf-op mutants, possibly reflecting recent activation outside the endoneurium before entering the nerve. Our findings demonstrate that M-CSF is crucial for the activation, in situ increase and myelin phagocytosis of both long-term and short-term resident endoneurial macrophages in P0+/- myelin mutants. M-CSF is, therefore, considered as a target candidate for therapeutic strategies to treat human demyelinating neuropathies.

TNFalpha mediates Schwann cell death by upregulating p75NTR expression without sustained activation of NFkappaB.

Administration of tumour necrosis factor alpha (TNFalpha) to axotomised mouse neonatal sciatic nerves increased Schwann cell apoptosis in the distal nerve segments, 5-fold greater than axotomy alone. TNFalpha upregulated the low affinity neurotrophin receptor, p75NTR, indicative of phenotype reversion in Schwann cells. Furthermore, re-expression of p75NTR and downregulation of the pro-myelinating transcription factor, Oct 6, in Schwann cells occurred by treatment with TNFalpha, even after the maturation of these cells with brain derived neurotrophic factor (BDNF). TNFalpha treatment of Schwann cells produced only a transient activation of NFkappaB. More importantly, in NFkappaB (p65) mutant mice, axotomy increased Schwann cell apoptosis further than that seen in mice expressing NFkappaB (p65), implicating a survival role for NFkappaB. Collectively, these data suggest that TNFalpha can potentiate Schwann cell death through the modulation of their phenotype. Immature Schwann cells express a high level of p75NTR and as a consequence are susceptible to extracellular death stimuli because of the lack of sustained NFkappaB translocation.

The organizational and activational effects of sex hormones on tactile and thermal hypersensitivity following lumbar nerve root injury in male and female rats.

Considerable evidence exists for sex differences in human pain sensitivity. Women typically report a higher incidence of various painful conditions and report that the conditions are more painful when compared to men. In the present study, we sought to determine whether sex differences in pain sensitivity are observed using a lumbar radiculopathy model of low back pain in the rat and whether removal or alteration of gonadal hormones at specific timepoints can modulate these sex differences. Pubertal and adult male and female Sprague-Dawley rats were castrated 2 or 6 weeks prior to L5 nerve root injury to determine the activational hormonal effects. In a separate study, neonatal male and female Sprague-Dawley rats were either castrated or injected with testosterone, respectively, on postnatal day one to determine the organizational effects of gonadal hormones on L5 nerve root injury-induced behavioral hypersensitivity. Our results demonstrate that there was a statistically significant sex difference in the magnitude of mechanical allodynia and thermal hyperalgesia following experimentally induced radiculopathy in the rat: females demonstrated decreased thresholds to tactile and thermal stimuli as compared to males. Furthermore, the enhanced female hypersensitivity was reversed in pubertal and adult animals ovariectomized 6 weeks, but not 2 weeks prior to L5 nerve root injury. Our results demonstrate that the activational effects of gonadal hormones mediate the enhanced female tactile and thermal hypersensitivity following L5 nerve root injury. These results suggest that manipulation of gonadal hormones may be a potential source for novel therapies for chronic pain in women.

Decreased sensory neuropeptide release in isolated bronchi of rats with cisplatin-induced neuropathy.

We studied if attenuated neurogenic bronchoconstriction was associated with a change in sensory neuropeptide release in preparations from rats with cisplatin-induced neuropathy. Electrical field stimulation (100 stimuli, 20 V, 0.1 ms, 20 Hz) induced an increase in the release of somatostatin, calcitonin gene-related peptide (CGRP) and substance P determined by radioimmunoassay from baseline 0.18+/-0.01, 0.17+/-0.01 and 0.86+/-0.02, to 0.59+/-0.02, 1.77+/-0.04 and 5.96 fmol/mg wet tissue weight, respectively, in organ fluid of tracheal tubes from rats. This was significantly attenuated to post-stimulation values of 0.36+/-0.02, 0.45+/-0.02, 4.68+/-0.24 fmol/mg wet tissue weight for somatostatin, CGRP, and substance P, respectively, with a significant decrease in field stimulation-induced contraction of bronchial preparations from animals 11 days after a 5-day treatment period with cisplatin (1.5 mg/kg i.p. once a day). The cisplatin-treated animals developed sensory neuropathy characterized by a 40% decrease in femoral nerve conduction velocity. The results show that a decrease in tracheo-bronchial sensory neuropeptide release associates with feeble bronchomotor responses in rats with cisplatin-induced sensory neuropathy.

Localization of major gangliosides in the PNS: implications for immune neuropathies.

Antibodies targeting major gangliosides that are broadly distributed in the nervous system are sometimes associated with clinical symptoms that imply selective nerve damage. For example, anti-GD1a antibodies are associated with acute motor axonal neuropathy (AMAN), a form of Guillain-Barré syndrome that selectively affects motor nerves, despite reports that GD1a is present in human axons and myelin and is not expressed differentially in motor versus sensory roots. We used a series of high-affinity monoclonal antibodies (mAbs) against the major nervous system gangliosides GM1, GD1a, GD1b and GT1b to test whether any of them bind motor or sensory fibres differentially in rodent and human peripheral nerves. The following observations were made. (i) Some of the anti-GD1a antibodies preferentially stained motor fibres, supporting the association of human anti-GD1a antibodies with predominant motor neuropathies such as AMAN. (ii) A GD1b antibody preferentially stained the large dorsal root ganglion (DRG) neurones, in keeping with the proposed role of human anti-GD1b antibodies in sensory ataxic neuropathies. (iii) Two mAbs with broad structural cross-reactivity bound to both gangliosides and peripheral nerve proteins. (iv) Myelin was poorly stained; all clones stained axons nearly exclusively. Our findings suggest that anti-ganglioside antibody fine specificity as well as differences in ganglioside accessibility in axons and myelin influence the selectivity of injury to different fibre systems and cell types in human autoimmune neuropathies.

Ganglioradiculitis (sensory neuronopathy) in a dog: clinical, morphologic, and immunohistochemical findings.

A 9-year-old Labrador Retriever was diagnosed with ganglioradiculitis (sensory neuronopathy). This idiopathic disease of mature dogs is characterized by a profound loss of sensory nerve function due to mononuclear inflammatory infiltration of peripheral ganglia and spinal nerve roots, with destruction of sensory neurons. Immunohistochemistry demonstrates that the infiltrating cells are primarily T lymphocytes and that immunoglobulins are not present on the cell membranes of affected neurons. The pathogenesis of ganglioradiculitis remains unclear, but the evidence points to a cell-mediated immune mechanism.

Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing.

Axon calibre is crucial to efficient impulse transmission in the peripheral nervous system. Neurofilament numbers determine gross axonal diameter, but intra-axonal distribution depends on the phosphorylation status of neurofilament sidearms. Myelin-associated glycoprotein (MAG) has been implicated in the signalling cascade controlling neurofilament phosphorylation and hence in the control of axon calibre. In an electron microscopic morphometric study we measured nearest neighbour neurofilament distances (NNND) in the axons of sural nerves from patients with anti-MAG paraproteinaemic neuropathies and compared these with normal human sural nerves and those from patients with Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Axon calibre was similar in all groups. In normal human sural nerves, axonal NNND was correlated with axonal diameter (r = 0.56). In diseased axons this correlation did not exist. The NNND was significantly reduced in demyelinated axons (30.5+/-2.2 nm) and those with widely spaced myelin (28.9+/-1.3 nm) from patients with anti-MAG antibodies compared with normal axons from normal patients (39.8+/- 3.2 nm) or those with demyelinating neuropathy (35.8+/-4.6 nm). This reinforces the hypothesis that MAG is involved in the control of neurofilament spacing through sidearm phosphorylation and demonstrates a MAG-mediated pathogenic effect of the anti-MAG antibody in peripheral nerves.

Autoimmunity and inflammation in the peripheral nervous system.

Peripheral Nerve Society Biennial Meeting, organized in conjunction with the Austrian Federal Ministry of Education, Research and Culture, held at Telfs, Tyrol, Austria from 8-12 September 2001.

Sublytic C5b-9-stimulated Schwann cell survival through PI 3-kinase-mediated phosphorylation of BAD.

Sublytic C5b-9 induces cell cycle activation, proliferation, and rescue from apoptosis in Schwann cells. The signaling pathways for C5b-9-mediated rescue were investigated. Following serum withdrawal, DNA fragmentation, detected by TUNEL and FACS analysis, was 56.7% +/- 7.3 and 91.9% +/- 2.4 in cultured sciatic nerve Schwann cells from 6-day-old rats after 18 h and 24 h, respectively. Apoptosis was confirmed by inhibition of DNA fragmentation in a dose-dependent manner by DMQD-CHO, a caspase-3 inhibitor. Treatment with sublytic C5b-9 generated with purified components (C5*9) or Ab+C7-depleted serum (C7dHS)+C7 rescued 89% and 86% of Schwann cells, respectively, as compared with cells treated with C5*6, C8, C9, or Ab+C7dHS. Sublytic C5b-9 increased Schwann cell PI-3 kinase and Akt activity maximally at 5 min 3.14 +/- 0.5-fold and 3.56 +/- 0.4-fold, respectively, over controls. ERK-1 activity was maximally stimulated 2.98-fold at 15 min. Inhibition of PI-3 kinase by LY294002 abrogated the C5b-9-mediated Schwann cell rescue from apoptosis, while inhibition of ERK-1 with PD098,059 did not. PI-3 kinase-Akt pathway activation by C5b-9 induced, within 15 min, a 6.34 +/- 1.2-fold increase in BAD phosphorylation at Ser 136, but not at Ser 112. Downstream Bcl-x(L) protein was increased 2.61-fold +/- 0.34-fold by 18 h and 3.9-fold +/- 0.84-fold by 24 h over controls. LY294002 prevented both BAD phosphorylation at Ser 136 and Bcl-x(L) protein induction, while PD098,059 did not. Our data indicated that sublytic C5b-9 rescued Schwann cell from apoptosis via activation of PI-3 kinase-Akt, BAD phosphorylation on Ser 136 and increased expression of Bcl-x(L). Sublytic C5b-9 detected on Schwann cell in vivo during inflammatory neuropathy may facilitate survival of Schwann cell capable of remyelination.

[Relevant antibodies in dysimmune neuropathies]. / Anticuerpos relevantes en neuropatías disinmunes.

INTRODUCTION: In the last 15 years a number of autoantibodies against antigens of the peripheral nervous system have been associated, in some cases, to specific clinical features. DEVELOPMENT: Antibodies to MAG or gangliosides have been described in neuropathies associated to monoclonal gammopathy or inflammatory polyneuropathies, such as Guillain-Barré syndrome or multifocal motor neuropathy. A lot of research is devoted to the characterization of known antibodies to glycolipids and the discovery of new ones. Furthermore, experimental models both with animals and in vitro preparations are performed in order to unravel the possible immunopathological role of these antibodies. CONCLUSIONS: It is very important to define the clinical features of these patients precisely in order to establish consistent associations between: presence of antibodies to specific antigens of the peripheral nervous system and clinical syndromes. A deeper knowledge of the antigens and antibodies involved in these neuropathies may be very helpful in the follow-up of these patients and also for future therapies.

Antibodies to GD1alpha and to GQ1beta in Guillain-Barré syndrome and the related disorders.

Certain species of anti-ganglioside antibodies are associated with specific clinical features in various neurologic diseases. Serum autoantibodies to these minor gangliosides were investigated in a number of neurological diseases in order to examine the biological functions of GD1alpha and GQ1beta. Eleven patients with Guillain-Barré syndrome had remarkably high IgG anti-GD1alpha antibody titers, but no GD1alpha was detected in human peripheral nerve. An absorption study showed that IgG anti-GD1alpha antibodies from eight of the 11 patients were significantly absorbed by GD1a and GM1b, indicative that the IgG anti-GD1alpha antibodies cross-react with GD1a and GM1b. Both GD1a and GM1b have been reported to be target molecules for serum antibodies in certain patients with Guillain-Barré syndrome. GD1alpha may induce the production of IgG anti-GD1alpha antibody which cross-reacts with GD1a or GM1b, and subsequently functions in the development of Guillain-Barré syndrome. The IgGs from six patients with Fisher's syndrome who had the anti-GQ1beta antibody had anti-GQ1b activity as well. All the patients had external ophthalmoplegia, but no GQ1beta was detected in the human oculomotor nerve, further evidence that GQ1b, not GQ1beta, is the molecule targeted by the autoantibody in Fisher's syndrome.

Chemokines and peripheral nerve demyelination.

It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell infiltration. In experimental allergic neuritis (EAN), an animal model for human Guillain-Barré syndrome (GBS) with mononuclear cell infiltration, we found by quantitative PCR that beta-chemokine messages were upregulated during the active stage. Moreover, an increase in the monocyte chemoattractant protein-1 (MCP-1) message was found in the preclinical stage of EAN, suggesting the critical role of MCP-1 for inducing mononuclear cell infiltrations in this model. Since many cell lineages other than immune cells can produce chemokines, this early upregulation of MCP-1 may be mediated by non-immune cells, probably endothelia or Schwann cells. To date, apart from MCP-1, only RANTES (Regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP)-1alpha have been examined in EAN and found to have similar kinetics of induction. Therefore, understanding the regulation of production of these chemokines as well as mechanisms of inhibiting chemokine/receptor interactions in the PNS may ultimately lead to disease-specific therapy for GBS and related demyelinating disorders.