tellurium and Peripheral-Nervous-System-Diseases

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

Accumulation of squalene in the CNS is observed after administration of tellurium and squalene has been proposed to be a mediator of tellurium encephaloneuropathy. The aim of this study was to investigate the effects of squalene on the central and peripheral nervous systems in rat at the ultrastructural level. Squalene was administered at a dose of 20 g/kg body weight, once daily for 4 days, and the animals were sacrificed 7 days and 30 days after the initiation of the experiment. After 7 days a mild swelling of mitochondria and dilation of the Golgi complex cisterns in few neurons in the cerebral cortex and hippocampus were observed. The swelling of astrocytes and their processes was also seen. Some myelin sheaths in the cerebral white matter were disintegrated. In the peripheral nervous system (the sciatic nerve), a damage of the Schwann cells, a destruction of the myelin sheaths, and lipid-like deposits between myelin lamellae causing a secondary compression of axons were present. Squalene administration caused a stimulation of fibroblast to synthesize collagen and an activation of macrophages in the perineurium. After 30 days, the lipid-like material was present in some neurons as well as in the myelin sheaths in the central nervous system. Endothelial cells were hypertrophic and a few demonstrated features of apoptosis. Endothelial cell hypertrophy caused a narrowing of vessel lumen associated with an aggregation of blood morphological elements. Disturbances in myelination and swelling of astrocytic processes persisted in the central nervous system. In the peripheral nervous system, lipid-like deposits were localized in some fibroblasts and extracellularly between the collagen fibers in the perineurium. In conclusion, our electron microscopic studies indicate that squalene produces characteristic pathological changes both in the central and peripheral nervous systems. However, these alterations differ in some aspects (changes in endothelia, accumulation of lipid-like material) from the known features of tellurium encephaloneuropathy.

Topics: Animals; Astrocytes; Brain; Brain Diseases; Injections, Subcutaneous; Lipids; Male; Microscopy, Electron; Organelles; Peripheral Nervous System; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Squalene; 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

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

A peripheral neuropathy characterized by a transient demyelinating/remyelinating sequence results when young rats are fed a tellurium-containing diet. The neuropathy occurs secondary to a systemic block in cholesterol synthesis. Squalene accumulation suggested the lesion was at the level of squalene expoxidase, a microsomal monooxygenase that uses NADPH cytochrome P450 reductase to receive its necessary reducing equivalents from NADPH. We have now demonstrated directly specificity for squalene epoxidase; our in vitro studies show that squalene epoxidase is inhibited 50% in the presence of 5 microM tellurite, the presumptive in vivo active metabolite. Under these conditions, the activities of other monooxygenases, aniline hydroxylase and benzo(a)pyrene hydroxylase, were inhibited less than 5%. We also present data suggesting that tellurite inhibits squalene epoxidation by interacting with highly susceptible -SH groups present on this monooxygenase. In vivo studies of specificity were based on the compensatory response to feeding of tellurium. Following tellurium intoxication, there was up-regulation of squalene epoxidase activity both in liver (11-fold) and sciatic nerve (fivefold). This induction was a specific response, as demonstrated in liver by the lack of up-regulation following exposure to the nonspecific microsomal enzyme inducer, phenobarbital. As a control, we also measured the microsomal monooxygenase activities of aniline hydroxylase and benzo(a)pyrene hydroxylase. Although they were induced following phenobarbital exposure, activities of these monooxygenases were not affected following tellurium intoxication, providing further evidence of specificity of tellurium intoxication for squalene epoxidase.

Topics: Aniline Hydroxylase; Animals; Benzopyrene Hydroxylase; Liver; NADPH-Ferrihemoprotein Reductase; Oxygenases; Peripheral Nervous System Diseases; Rats; Sciatic Nerve; Squalene Monooxygenase; Sulfhydryl Compounds; 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

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

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