tellurium and Demyelinating-Diseases

Primary demyelination is an important component of a number of human diseases and toxic neuropathies. Animal models of primary demyelination are useful for isolating processes involved in myelin breakdown and remyelination because the complicating events associated with axonal degeneration and regeneration are not present. The tellurium neuropathy model has proven especially useful in this respect. Tellurium specifically blocks synthesis of cholesterol, a major component of PNS myelin. The resulting cholesterol deficit in myelin-producing Schwann cells rapidly leads to sychronous primary demyelination of the sciatic nerve, which is followed by rapid synchronous remyelination when tellurium exposure is discontinued. Known alterations in gene expression for myelin proteins and for other proteins involved in the sequence of events associated with demyelination and subsequent remyelination in the PNS are reviewed, and new data regarding gene expression changes during tellurium neuropathy are presented and discussed.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Humans; Macrophages; Myelin Proteins; Myelin Sheath; Peripheral Nervous System; RNA, Messenger; Tellurium

A compound may be "developmentally neurotoxic" because it interferes with a metabolic step exclusively or preferentially expressed during development in a particular class of neural cells. The initial metabolic specificity is often complicated by: (1) secondary responses in the affected cells, (2) involvement of other functionally-related cell types, and (3) the presence of compensatory and/or regenerative responses. In this context we study tellurium, which systemically blocks cholesterol biosynthesis at the squalene epoxidase step. Because of the high demand in developing peripheral nerves for newly synthesized cholesterol required for myelin assembly, this metabolic block leads to demyelination of the sciatic nerve. This insult is confounded by the fact that the myelin-forming Schwann cells do not upregulate their cholesterol biosynthetic pathway. This is contrary to expectations; liver (the main source of cholesterol for many tissues outside the nervous system) upregulates synthesis of cholesterol and overcomes the metabolic block. The shortage of cholesterol in Schwann cells results in an immediate secondary response down-regulation of steady-state mRNA levels for specific myelin proteins. Remyelination occurs after cessation of tellurium exposure. This model of primary demyelination allows study of Schwann-cell specific responses during the processes of myelin breakdown and subsequent steps leading to remyelination, without the complications of axonal degeneration and regeneration. Because tellurium specifically blocks the synthesis of a major required membrane component, it is also well suited for examining the coordinate control of membrane synthesis and assembly at the genomic level.

Topics: Animals; Cholesterol; Demyelinating Diseases; Gene Expression; Rats; Tellurium

Ingestion of tellurium (Te), a toxic element, produces paralysis of the hind limbs in weanling rats that is due to temporary, segmental demyelination of the sciatic nerves bilaterally. Weanling rats were fed a 1.1% elemental Te diet and sacrificed at various time points for histological and magnetic resonance (MR) analysis of the sciatic nerves. No controls exhibited impairments of the hind limbs, whereas Te-treated animals became progressively impaired with increased Te exposure. Toluidine blue-stained nerve sections of Te-treated animals showed widened endoneurial spaces, disrupted myelin sheaths, swollen Schwann cells, and a few instances of axonal degeneration. Te decreased healthy myelin by 68% and increased percent extracellular matrix by 45% on day 7. MR experiments showed a decrease in the area of the short T2 component, an increase in average T1, and an increase in the position of the intermediate T2 component in Te-treated nerves. The correlation coefficient for healthy myelin and average T1 was 0.88 and that for healthy myelin and the area underneath the short T2 component was 0.77. The area of the short T2 component has been postulated as the best measure of the process of demyelination.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Peripheral Nervous System Diseases; Radiography; Rats; Rats, Inbred Lew; Sciatic Nerve; Tellurium

Changes in the magnetic resonance (MR) parameters of demyelinated neural tissue were measured in vitro using an experimental animal model. A tellurium (Te) diet was applied to weanling rats to induce the demyelination process in the sciatic nerve. The quantitative MR parameters, such as T(1), T(2) relaxation time constants and magnetization transfer (MT) were measured each day after applying the Te diet (up to 7 days) and were found to be substantially different from those of normal nerves. An increase in the average T(1) and T(2) was observed along with a decrease in the MT ratio (MTR) and the quantitative MT parameter M(0B), which describes the semisolid pool of protons. Most of the MR parameters correlated very well with the myelin fraction of neural tissue evaluated by quantitative histopathology. The T(2) relaxation spectrum provided the most efficient quantitative assessment of changes in neural tissue microstructure and its analysis resulted in a powerful tool to distinguish the processes of demyelination and inflammation. In comparison, the MT measurements were less successful.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Image Interpretation, Computer-Assisted; In Vitro Techniques; Magnetic Resonance Imaging; Rats; Rats, Inbred Lew; Reproducibility of Results; Sciatic Nerve; Sciatic Neuropathy; Sensitivity and Specificity; Tellurium

We have used an experimental model of tellurium (Te)-induced demyelinating neuropathy in the rat to study cellular mechanisms involved in the early response of myelinating Schwann cells (SCs) to injury, prior to demyelination. Starting at postnatal day 21, weaned rats were fed a diet containing 1.1% elemental Te. The animals were killed daily within the 1st week of Te diet and the sciatic nerves were processed for the ultrastructural and immunocytochemical studies. Immunohistochemistry revealed that Te induces an increased nuclear expression of c-Fos in SCs. By electron microscopy analysis, the early cytoplasmic alteration was a dramatic disorganization of the rough endoplasmic reticulum (ER) with cisternal dilations and redistribution and loss of membrane-bound ribosomes. This was followed by a prominent activation of the macroautophagy in SCs. This process involved the formation of autophagosomes containing well-preserved cell organelles, autolysosomes with cellular remnants in various phases of degeneration and lysosomes. Te treatment also induced the expression of free ubiquitin in the perikaryal region of the SC cytoplasm. Immunogold electron microscopy showed the subcellular distribution of ubiquitin in the cytosol, around of dilated ER cisterns and in the matrix of autolysosomes and residual bodies. At the nucleolar level, fibrillarin immunofluorescence revealed nucleolar segregation in SCs exposed to Te. The ultrastructural study confirmed the segregation of the nucleolar components with a peripheral distribution of the dense fibrillar component. These results support the hypothesis that the depletion of cholesterol induced by Te treatment triggers a stress response in myelinating SCs mediated by immediate early genes of the fos family. The cellular response includes a severe disruption of the protein synthesis machinery, namely the rough ER and nucleolus, with the subsequent activation of both ubiquitin and autophagic pathways of proteins and cell organelle degradation. This cytoplasmic remodeling may represent a cytoprotective mechanism in the response of SCs to a neurotoxic stress. Furthermore, it must be a prerequisite for the induction of phenotypic changes and cell repair mechanisms in SCs.

Topics: Animals; Autophagy; Cell Nucleolus; Cell Nucleus; Cytoplasm; Demyelinating Diseases; Endoplasmic Reticulum, Rough; Immunohistochemistry; Lysosomes; Male; Microscopy, Immunoelectron; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Ribosomes; Schwann Cells; Tellurium; Ubiquitins

We present a cytological, immunocytochemical, and biochemical study of the cell death of mature myelinating Schwann cells (SCs) in the primary demyelinating neuropathy induced by tellurium (Te). Weaned rats were fed a diet containing 1.1% elemental Te. The animals were killed daily within the first week of Te diet. After 4 to 6 days of Te treatment some SCs underwent degeneration and necrosis. By electron microscopy analysis, degenerating SCs showed chromatin condensation, detachment from the nuclear envelope of condensed chromatin clumps, aggregation of interchromatin granule clusters, formation of intranuclear bundles of microfilaments, and cytoplasmic vesiculation. By confocal laser fluorescence microscopy, chromatin regions were stained with the TUNEL method for in situ labeling of DNA fragmentation and exhibited a progressive reduction of histone signal. In addition, splicing small nuclear ribonucleoprotein (snRNP) factors were redistributed in a few large nuclear domains and bright foci of intranuclear actin were observed. DNA electrophoresis revealed a smear pattern of DNA fragmentation in sciatic nerve samples from Te-treated animals. Upon Te treatment, no degradation of the caspase substrates poly (ADP-ribose) polymerase and lamin B was detected by Western blots or immunocytochemistry, respectively. The peculiar structural rearrangement of the transcription and splicing machinery as well as the vesicular degeneration of the cytoplasm in degenerating SCs support an autophagic cell death of the necrotic type. Unlike the apoptosis of pre-remyelinating SCs (11), this caspase independent cell death of necrotic type involves mature pre-demyelinating SCs and eliminates SCs injured by the neurotoxic effect of Te.

Topics: Actins; Animals; Caspases; Cell Nucleus; Demyelinating Diseases; DNA; DNA Fragmentation; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Male; Necrosis; Rats; Rats, Sprague-Dawley; RNA Splicing; Schwann Cells; Tellurium

We have used an experimental model of tellurium(Te)-induced demyelinating neuropathy in the rat to study cellular mechanisms involved in regulating Schwann cell (SC) numbers during remyelination. Starting at postnatal day 21, weaned rats were fed a diet containing 1.1% elemental Te. Following 7 days of Te treatment and at several time points of post-tellurium treatment (PTe), the animals were processed for ultrastructural analysis, SC nuclei quantification and teased fibre preparations. It is well-established that Te induces a transient demyelinating/remyelinating sequence in sciatic nerves. The loss of the myelin sheath in this neuropathy produces active proliferation and overproduction of immature SCs. By electron microscopy analysis most mitotic SCs were located along demyelinated segments. Quantitative determination of SC nuclei per transverse section of sciatic nerve revealed a dramatic increase of SCs at 2 days PTe relative to control nerves. The number of SC nuclei then decreased progressively during the long-term period of recovery studied (330 days PTe). In Te-treated rats, SCs undergoing cell death were regularly found within the nerve fibre compartment, especially on demyelinated segments. Dying cells exhibited morphological features of apoptosis and appeared enclosed by lamellar processes of adjacent healthy SCs in extracellular compartments. Both healthy immature SCs and endoneurial macrophages were involved in the phagocytosis of apoptotic SCs. Particularly during remyelination, supernumerary endoneurial SCs were observed surrounding myelinated fibres. These cells progressively became atrophic with a morphological phenotype similar so that of "onion bulb" cells. On the other hand, teased fibre measurements revealed a remarkable permanent internodal shortening in remyelinated fibres from Te-treated sciatic nerves. These results indicate that a portion of redundant immature SCs are susceptible to elimination by apoptosis. However, other distinct biological mechanisms such as the persistence of supernumerary SCs in the endoneurium and the shortening of internodal lengths are also involved in regulating SC numbers during the remyelination stage.

Topics: Animals; Apoptosis; Cell Nucleus; Demyelinating Diseases; Disease Models, Animal; Male; Microscopy, Electron; Myelin Sheath; Ranvier's Nodes; Rats; Rats, Sprague-Dawley; Schwann Cells; Tellurium

Following injury to the peripheral nervous system, circulating monocytes/macrophages are recruited to the damaged tissue, where they play vital roles during both nerve degeneration and subsequent regeneration. Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C or beta-chemokine family, is a powerful leukocyte recruitment/activation factor that is relatively specific for monocytes/macrophages. Because these are the predominant leukocyte type recruited by injured nerve, we hypothesized that upregulation of MCP-1 expression is involved in recruitment of these cells. Indeed, assay of steady-state levels of MCP-1 mRNA in rat sciatic nerve during tellurium-induced primary demyelination indicated up-regulation of this chemokine with a peak after 3 days of tellurium exposure, preceding the peak of accumulation of phagocytic macrophages (assayed as lysozyme mRNA levels) by 6 days. Increasing levels of MCP-1 mRNA expression, induced by increasing levels of tellurium exposure, resulted in corresponding increases in subsequent recruitment of macrophages. In situ hybridization suggested that MCP-1 mRNA was localized in Schwann cells. No expression of MIP-2, which is a C-X-C or alpha-chemokine that is specific for recruitment of neutrophils, was detected, consistent with the lack of recruitment of significant numbers of these cells. In addition, we also investigated the response seen following nerve transection (axonal degeneration and secondary demyelination with no subsequent regeneration) and nerve crush (degeneration followed by regeneration). In these latter two nerve injury models, there was also a marked, early up-regulation of MCP-1 mRNA, with a time course that is compatible with a role for this chemokine in macrophage recruitment. We conclude that MCP-1 is involved in recruiting monocytes/macrophages to injured peripheral nerve and that the specificity of leukocyte types recruited results from specificity of chemokine production.

Topics: Animals; Blotting, Northern; Chemokine CCL2; Demyelinating Diseases; Immunohistochemistry; In Situ Hybridization; Macrophages; Male; Nerve Crush; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sciatic Nerve; Tellurium

Exposure of weanling rats to a diet containing 1% elemental tellurium causes segmental demyelination of peripheral nerve, and an inhibition of squalene epoxidase. This inhibition is thought to be the mechanism of action leading to demyelination. Tellurite appears to be the active inhibitory species in a cell-free system but the active species in vivo is unknown. We examined potassium tellurite (K2TeO3) and three organotellurium compounds for their ability to inhibit squalene epoxidase in Schwann cell cultures and to induce demyelination in weanling rats. K2TeO3 had no effect on squalene epoxidase activity in cultured Schwann cells and caused no demyelination in vivo. All three organotellurium compounds caused inhibition of squalene epoxidase in vitro and caused demyelination in vivo. (CH3)2TeCl2 was the most potent of these compounds and its neuropathy most resembled that caused by elemental tellurium. These data are consistent with the hypothesis that tellurium-induced demyelination is a result of squalene epoxidase inhibition and suggest that a dimethyltelluronium compound may be the neurotoxic species presented to Schwann cells in vivo.

Topics: Animals; Cholesterol; Demyelinating Diseases; Peripheral Nervous System Diseases; Rats; Schwann Cells; Tellurium

To investigate the influence of squalene on the nervous system, adult male Wistar rats were injected with squalene subcutaneously with 20 g/kg of the body weight for 4 consecutive days. After 7 or 30 days from the initiation of the experiment, brain and ischiadic nerves were harvested for electron microscopy. Squalene affected mostly PNS targeting Schwann cells and myelin sheaths. Accumulation of lipid-like droplets in the myelin sheaths in the PNS and in the neurons in the brain cortex, hypertrophy of endothelium, and sometimes endothelial apoptosis in blood vessels, and increased synthesis of collagen in the ischiadic nerve were characteristic for developed squalene encephaloneuropathy.

Topics: Animals; Apoptosis; Central Nervous System Diseases; Demyelinating Diseases; Lipids; Male; Myelin Sheath; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Schwann Cells; Squalene; Tellurium

Demyelination is a prominent feature in nerve biopsies of patients with diabetic neuropathy. The mechanism is unknown because diabetic rodents, unlike humans, do not consistently develop segmental demyelination. We examined how diabetes influences toxicant-induced demyelination, remyelination, Schwann cell nerve growth factor receptor (p75) expression, and endoneurial macrophage apolipoprotein E (apo E) synthesis in diabetic rats. Postnatal day 17 (P17) rats were given 110 mg/kg streptozotocin intraperitoneally and then fed a diet containing metallic tellurium (Te) from P20 to P27 to induce demyelination. Transverse electron micrographs and immunostained longitudinal cryosections were prepared from sciatic nerve during demyelination and remyelination. Diabetic rats had a mean serum glucose concentration of 490 mg/dl and consumed equivalent doses of peroral Te. The number of demyelinated fibers in electron micrographs was increased significantly by 17% (P < .0011). Endoneurial density of p75-stained Schwann cells was increased in diabetic rats in proportion to the increased number of injured internodes. Density of apo E- and ED1-positive macrophages also was significantly increased in diabetes. There was no delay in macrophage myelin clearance. and remyelination was not compromised. Increased Schwann cell vulnerability to stress, by increasing the turnover rate of myelinated units, may explain why myelin defects accumulate after long-standing diabetes.

Topics: Animals; Apolipoproteins E; Demyelinating Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Female; Macrophages; Male; Metabolic Clearance Rate; Myelin Proteins; Nerve Regeneration; Rats; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Schwann Cells; Tellurium; Up-Regulation

The efficacy of garlic as a lipid-lowering agent is being increasingly recognized, but the biochemical mechanisms underlying this action are currently unknown. It is proposed that organic tellurium compounds, which are found in high concentration in fresh garlic buds, may contribute to this action by inhibiting squalene epoxidase, the penultimate enzyme in the synthetic pathway of cholesterol. Weanling rats fed a diet rich in tellurium develop a demyelinating polyneuropathy due to inhibition of this enzyme in peripheral nerves. Chronic exposure to small amounts of tellurium found in garlic might reduce endogenous cholesterol production through inhibition of hepatic squalene epoxidase and so reduce cholesterol levels. Tellurium may also contribute to the characteristic odour of garlic since the most obvious clinical sign of tellurium poisoning is a garlic-like odour.

Topics: Animals; Anticholesteremic Agents; Demyelinating Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Garlic; Humans; Liver; Models, Biological; Oxygenases; Peripheral Nervous System Diseases; Plants, Medicinal; Rats; Squalene Monooxygenase; Tellurium

We observed demyelination and rapid reparative remyelination in the cerebral white matter, cortex and optic nerve of adult rats intoxicated with sodium tellurite (1.25 and 6.25 mg/kg Te4+). Hypomyelination dominated by the seventh day and its intensity was dependent on the dose Te4+. Reparative myelination was not completed in the brains 30 days after the intoxication with tellurium. In addition to myelin changes, signs of neuronal and astrocytic damage were seen: dark neurons and swelling of the astrocytic processes and synapses in the cerebral cortex. We postulate that tellurium evokes not only the myelin sheath and a myelin forming glia damage but also ultrastructural changes in some axons, and reaction of fibrillar astrocytes.

Topics: Animals; Astrocytes; Axons; Central Nervous System Diseases; Cerebral Cortex; Demyelinating Diseases; Microscopy, Electron; Myelin Sheath; Optic Nerve; Rats; Rats, Wistar; Tellurium

Initiation of remyelination is a promising therapeutic strategy to treat patients with demyelinating diseases, but specific factors that control remyelination are not clear. We first reported that expression of nerve growth factor receptor (NGFR) was increased during initiation of remyelination (Fan and Gelman, Journal of Neuropathology and Experimental Neurology 49: 312, 1990). In this study, we characterized the timing and cellular localization of NGFR expression in a model of segmental demyelination and remyelination using immunohistochemistry and monoclonal antibody 192-IgG, and compared it to an axonal neuropathy. At the onset of demyelination induced by tellurium (Te) poisoning, NGFR antigenicity was selectively expressed within and around demyelinating internodes in rat sciatic nerve. Dual fluorescence staining with myelin-specific antigen showed that NGFR colocalized with demyelinated internodal units with relative specificity; Schwann cell S-100 protein showed a concomitant down-regulation in injured internodes. Peak expression of NGFR occurred during the transition between demyelination and remyelination (day 8 of Te), then declined exponentially. NGFR expression was most prominent in the cytoplasm of daughter Schwann cells as they established contact with denuded axons, and was sharply repressed as compact myelin began to accumulate. Rare colocalization with neurofilament antigens revealed intraxonal deposits of NGFR in segmental demyelination. In the nerve crush model, Schwann cell NGFR expression was not segmentally distributed and was upregulated for a longer period of time. Our data establish that NGFR expression in the peripheral nervous system is not strictly linked to axon elongation, and that it probably functions during the initiation of myelination.

Topics: Animals; Cell Communication; Demyelinating Diseases; Denervation; Gene Expression Regulation; Male; Myelin Sheath; Nerve Crush; Nerve Fibers, Myelinated; Nerve Growth Factors; Nerve Regeneration; Rats; Receptors, Cell Surface; Receptors, Nerve Growth Factor; Schwann Cells; Sciatic Nerve; Tellurium; Up-Regulation

Exposure of developing rats to tellurium results in a highly synchronous segmental demyelination of peripheral nerves with sparing of axons; this demyelination is followed closely by a period of rapid remyelination. Demyelination occurs subsequent to a tellurium-induced block in the synthesis of cholesterol, the major myelin lipid. We utilized the techniques of Northern blotting, in situ hybridization, and immunocytochemistry to examine temporal alterations in Schwann cell gene expression related to demyelination and remyelination. Tellurium-induced demyelination is associated with downregulation of myelin protein expression and a corresponding upregulation of NGF receptor (NGF-R) and glial fibrillary acidic protein (GFAP) expression. Steady-state mRNA levels (expressed on a "per nerve" basis) for P0, the major myelin protein, were decreased by about 50% after 5 d of tellurium exposure, while levels of mRNA for NGF-R and GFAP were markedly increased (about 15-fold). In situ hybridization of teased fibers suggested that the increase in steady-state mRNA levels for NGF-R was primarily associated with demyelinated internodes and not with adjacent unaffected internodes. Although P0 message was almost totally absent from demyelinating internodes, it was also reduced in normal-appearing internodes as well. This suggests that limiting the supply of a required membrane component (cholesterol) may lead to partial downregulation of myelin gene expression in all myelinating Schwann cells. In partially demyelinated internodes, NGF-R and GFAP immunofluorescence appeared largely confined to the demyelinated regions. This suggests specific targeting of these proteins to local areas of the Schwann cell where there is myelin loss. These results demonstrate that demyelination is associated with reversion of the affected Schwann cells to a precursor cell phenotype. Because axons remain intact, our results suggest that these changes in Schwann cell gene expression do not require input from a degenerating axon, but instead may depend on whether concerted synthesis of myelin is occurring.

Topics: Animals; Demyelinating Diseases; Gene Expression; Glial Fibrillary Acidic Protein; Immunohistochemistry; Intracellular Membranes; Male; Myelin P0 Protein; Myelin Proteins; Nerve Fibers; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Nerve Growth Factor; RNA, Messenger; Schwann Cells; Tellurium; Tissue Distribution

Weanling rats fed a diet containing tellurium develop a peripheral neuropathy characterized by a highly synchronous primary demyelination; this demyelination is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis. Expression of mRNA for the major structural proteins of PNS myelin, myelin basic protein and P0, is coordinately down-regulated during the demyelinating phase and then up-regulated during the remyelinating phase (Toews et al., J. Neurosci. Res., 26 (1990) 501-507). We now report tellurium-induced alterations in gene expression for several proteins which are not major structural components of myelin in the peripheral nervous system. Expression of mRNA for nerve growth factor receptor in sciatic nerve was very low in control animals, but was markedly up-regulated after 3-5 days of exposure to tellurium, a time corresponding to the beginning of demyelination. Levels remained elevated during the subsequent period of remyelination. Expression of mRNA for SCIP (a presumptive transcription factor) was also up-regulated in sciatic nerve following tellurium exposure, with a time course similar to that for nerve growth factor receptor. When examined as a fraction of total RNA, steady-state mRNA levels for 2',3'-cyclic nucleotide 3'-phosphodiesterase and the myelin proteolipid protein were decreased during the demyelinating phase; however, this decrease could be largely accounted for by increased levels of total RNA. When analyzed on a 'per nerve' basis, steady-state mRNA levels for these two proteins were actually increased about 2-fold by 9 days after beginning tellurium exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Blotting, Northern; Demyelinating Diseases; Male; Myelin Proteins; Myelin Proteolipid Protein; Nerve Growth Factors; Nerve Tissue Proteins; Octamer Transcription Factor-6; Rats; Receptors, Cell Surface; Receptors, Nerve Growth Factor; RNA, Messenger; Sciatic Nerve; Tellurium; Time Factors; Transcription Factors

The synthesis and endoneurial distribution of apolipoproteins in response to myelin degradation was elucidated morphologically and biochemically in rodent models of segmental demyelination. At the onset of acute demyelination induced by tellurium (Te) poisoning, macrophages infiltrated the endoneurium and then began to express cytoplasmic immunoreactivity for apolipoprotein E (apo E). When demyelinating nerve slices were incubated with S35-methionine, radiolabeled apo E was released, showing that apo E was actively synthesized by the macrophages. Macrophages secreted apo E into the endoneurial spaces, leading to dense endoneurial accumulations. Other apolipoproteins (apo A1 and albumin) were not synthesized in the endoneurium, but they entered edematous nerves, presumably through an early breakdown in the blood-nerve barrier. During the phagocytosis of myelin, plasma-derived apolipoproteins accumulated within some of the macrophages. In chronic demyelination caused by lead poisoning, the cellular and extracellular distribution of apolipoproteins was similar to Te neuropathy; the amount of apo E accumulation and the macrophage density were proportional to the prevalence of active demyelination in teased fibers. Similar patterns of endoneurial apo E were present in an inherited form of demyelination in the twitcher mouse, after antibody-mediated demyelination, and in demyelination secondary to axonal degeneration. Human sural nerve biopsies had patterns of apolipoprotein E antigenicity that were comparable to the rodent models. We conclude that secretion of apo E by infiltrating macrophages is a generalized response to demyelination, and that endoneurial edema leads to the accumulation of certain plasma apolipoproteins within macrophages. These data suggest that endoneurial apolipoproteins and macrophages might mediate important functions in patients recovering from primary and secondary demyelination.

Topics: Animals; Apolipoproteins E; Demyelinating Diseases; Macrophages; Male; Nerve Degeneration; Nervous System; Nervous System Diseases; Rats; Sciatic Nerve; Tellurium

The appearance of endoneurial edema early in the evolution of tellurium neuropathy raises the possibility that a breakdown of the blood-nerve barrier (BNB) plays a role in the pathogenesis of the tellurium-induced demyelination. To investigate this possibility, we correlated the temporal onset of breakdown of the BNB with inhibition of cholesterol synthesis and ultrastructural abnormalities in sciatic nerve of weanling Long-Evans rats fed a diet containing 1.1% elemental tellurium. Permeability of the BNB was assessed with [125I]-albumin and horseradish peroxidase (HRP); cholesterol synthesis was assessed by incubating segments of sciatic nerve in vitro with [1-14C]acetate. Cholesterol synthesis was severely inhibited and labeled squalene was accumulating in sciatic nerve at 12 hr of tellurium exposure. The permeability of the BNB progressively increased between 24 hr and 72 hr of tellurium exposure. Membrane-delimited vacuoles, lipid droplets and cytoplasmic excrescences appeared in myelinating Schwann cells at 24 hr; demyelinating axons appeared at 48 hr of tellurium exposure. These observations suggest that factors other than BNB breakdown and vasogenic endoneurial edema are responsible for the initial Schwann-cell injury in tellurium neuropathy. However, the early onset of BNB breakdown may have a synergistic role in the pathogenesis of tellurium-induced demyelination.

Topics: Animals; Cholesterol; Demyelinating Diseases; Male; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sciatic Nerve; Tellurium

The frequency of demyelinated fibers in mixed nerve and cutaneous nerve and the relationship of the frequency of demyelination to internodal length were assessed in a model of tellurium neuropathy in the rat. Twenty-day-old Long-Evans rats were fed chow containing 1.25% elemental tellurium for seven days and subsequently killed at 34 or 41 days of age. Teased-fiber preparations revealed a higher frequency of demyelinated fibers in sciatic nerve (mixed nerve) than in sural nerve (cutaneous nerve). The frequency of demyelinated fibers was positively associated with internodal length in both nerves. The type of nerve (mixed or cutaneous) was not a significant predictor of the frequency of demyelinated fibers once internodal length had been taken into account. These data indicate that there is a hierarchy of vulnerability within the population of myelinating Schwann cells to tellurium toxicity, and that this hierarchy is related to internodal length. The hierarchy of vulnerability may reflect intrinsic differences among Schwann cells, such as the volume of myelin each cell is synthesizing and maintaining, or a gradient of unrecognized axonal abnormalities.

Topics: Animals; Demyelinating Diseases; Male; Peripheral Nervous System Diseases; Rats; Schwann Cells; Sciatic Nerve; Sural Nerve; Tellurium

Tellurium (Te) is a naturally occurring element with many industrial uses. Microinjection of 0.3 micrograms of potassium tellurite [K(2)TeO(3)] into the endoneurial space of rat tibial nerve causes a rapidly progressing focal conduction block as measured by the disappearance of the evoked compound muscle action potential (CMAP) of the intrinsic foot muscles following stimulation proximal to the injection site. Conduction block was fully established within 6 hours and persisted for approximately 7 days, followed by the appearance of low amplitude, long latency, temporally dispersed potentials. The proximal CMAPs increased in amplitude and decreased in latency and temporal dispersion until normalization by 28 days after injection. The distal CMAP showed a minimal decline in amplitude. Morphological observations showed splitting of myelin, especially in the paranodal regions, followed by accumulation of myelin debris in Schwann cells and macrophages. Although the exact mechanism remains unknown, this in vivo model provides a unique opportunity to study the electrophysiological and morphological correlates of an acutely evolving demyelinative process.

Topics: Animals; Demyelinating Diseases; Electric Stimulation; Evoked Potentials; Male; Muscle Contraction; Muscles; Neural Conduction; Rats; Rats, Inbred Strains; Tellurium; Tibial Nerve

Weanling rats fed a diet containing elemental tellurium became paralyzed of their hind legs based on segmental demyelination of the sciatic nerves. Recovery from the paralysis and remyelination took place despite continued receiving of the diet. The author could divide the process of demyelination and remyelination into four stages (Stage I-IV). The earliest changes were observed in the Schwann cell cytoplasm in which the Golgi complex revealed shrinkage, fragmentation and vacuolation. These changes soon involved the endoplasmic reticulum (Stage I). Degenerative changes of the Golgi complex and the endoplasmic reticulum were considered to disturb the active Schwann cell metabolism inhibiting the synthesis and maintenance of the myelin, resulted in disintegration and destruction of the myelin sheath (Stage II). Schwann cells proliferated around the demyelinated axons extending numerous elongated processes (Stage III). When remyelination began, only one simple shaped Schwann cell was associated with the axon. Remyelinated fibers were generally small in size, which was considered to be related to the formation of the short segments as well as to the Schwann cell proliferation (Stage IV).

Topics: Animals; Demyelinating Diseases; Myelin Sheath; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Schwann Cells; Tellurium

This is a study of DNA synthesis of Schwann cells during the demyelination and the remyelination of peripheral nerves secondary to the intoxication of young rats with tellurium (Te). 3H-thymidine uptake of Schwann cells begins on day 4, reaches a zenith on day 7, and ends before day 20 on the Te diet despite continuation of the diet. The chronology of pathologic events is that myelin breakdown leading to segmental demyelination occurs first, followed within 24--48 h by the appearance of paralysis and by the beginning of DNA synthesis by the Schwann cells. A quantitative study on isolated nerve fiber preparations showed that more Schwann cells are produced than necessary to cope with the remyelination and that only one of four to six Schwann cells present in the demyelinated area at day 12 will participate in the remyelinating process.

Topics: Animals; Autoradiography; Cell Division; Demyelinating Diseases; DNA; Female; Male; Peripheral Nerves; Rats; Schwann Cells; Tellurium; Time Factors

Elemental tellurium (TE) was included in the normal diet of 15-day-old rats and every day thereafter for 35 days. Within 24 hours a segmental demyelination was seen in the sciatic nerve. On the 2nd day, Te was localized in the cytoplasm of the Schwann cells. On the 3rd day paralysis of the hind legs appeared which lasted 7--10 days. The papralysis then disappeared and demyelination ceased, although the rats were still ingesting Te. After one week there was also slight demyelination in the brachial plexus. Motor nerve conduction velocities were reduced below the normal control range, but only after the rats had taken Te for a least 7 days. This peripheral neuropathy can only be induced in the rat by Te ingestion between the 15th and 35th days of post-natal life, not before or after this period of time.

Topics: Animals; Demyelinating Diseases; Motor Neurons; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Rats; Spectrophotometry, Atomic; Tellurium

Topics: Animals; Axons; Cytoplasm; Demyelinating Diseases; Inclusion Bodies; Macrophages; Microscopy, Electron; Myelin Sheath; Nerve Degeneration; Neurilemma; Rats; Rats, Inbred Strains; Schwann Cells; Sciatic Nerve; Tellurium; Time Factors

Topics: Animals; Animals, Newborn; Demyelinating Diseases; Hindlimb; Microscopy, Electron; Myelin Sheath; Paralysis; Rats; Schwann Cells; Sciatic Nerve; Spinal Nerves; Tellurium