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The experimental squalene encephaloneuropathy in the rat
Exp Toxic Patholl999; 51: 75-80 Gustav Fischer Verlag
IThe Laboratory of the Ultrastructure of the Nervous System and 2Department of Neuropathology ,Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
The experimental squalene encephaloneuropathy in the rat B. GAJKOWSKA 1, M. SMIALEK2, R. P. OSTROWSKI2 , P. PIOTROWSKI 2 , and M. FRONTCZAK-BANIEWICZ 1 With 10 figures Received: August 6,1997; Revised: November 8,1997; Accepted: November 17,1997
Address for correspondence: BARBARA GAJKOWSKA, PhD, The Laboratory of the Ultrastructure of the Nervous System, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland; Fax: +48226685532. Key words: Squalene; Tellurium; Encephaloneuropathy; Endothelium; Astrocytes.
Summary
Introduction
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 ofaxons 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.
Squalene epoxydase (EC. 1. 1. 1.34 ) catalyzes the conversion of squalene (2,6,1O,15,23-hexamethyl-2,6,1O,14, 18,22-tracosohexaene) into 2,3-epoxysqualene. It has been postulated that squalene epoxydase is inhibited by tellurium (Te) and that an excess of squalene is responsible for a transient paralysis of the hind legs in weaning rats and a peripheral, segmental neuropathy after administration of tellurium (LAMPERT et al. 1970; HARRY et al. 1989; WAGNER-RECIO et al. 1991). Our electron microscopic studies showed a vulnerability of the myelinated fibers to tellurium, both in the maturing and in the mature rat brain and in the optic nerve (SMIALEK et al. 1994; SMIALEK and GAJKOWSKA 1994). The dynamics of the electron microscopic changes in the central nervous system (CNS) after tellurium intoxication showed a degeneration of myelin sheaths and myelin forming glia with a secondary axonal damage (SMIALEK et al. 1994). The pathomechanism of tellurium neurotoxicity in the CNS differs from that in the peripheral nervous system (PNS), where Schwann cell damage with secondary myeloclasis is present (TAKAHASHI 1981). The aim of this work was to evaluate the ultrastructural changes in the CNS and the PNS of adult rats following squalene administration and to compare them with the known features of tellurium encephaloneuropathy.
Material and methods Ten male rats (strain Wistar, weight approximately 150 g) were injected subcutaneously with liquid squalene (Sigma) once daily 20 g/kg of the body weight about 3 ml for 4 consecutive days. Five animals were used as controls. After 7 or 30 days from the initation of the experiment, the frontal Exp Toxic Patho151 (1999) 1
75
Fig. 1. A border of cerebral white and grey matter in the frontal lobe, 7 days after administration of squalene. Note swelling of mitochondria (M), dilation of some endoplasmic reticulum channels, and ultrastructurally changed myelinated fibers with compressed axons (Ax). X 12500.
Fig. 2. Hippocampus, 7 days after squalene injection. Swollen astrocytic processes (A) around blood vessel and hypertrophy of endothelial cells (E). X 8500.
Fig. 3. Sciatic nerve, 7 days after squalene injection. Mild ultrastructural changes in some myelinated fibers and an activated fibroblast (F). X 8500.
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Exp Toxic Pathol51 (1999) 1
Fig. 4. Sciatic nerve, 7 days after squalene injection. Segmental disintegration of myelin laminae and formation of pathological myelin structures penetrating into the axon (Ax). X 12500.
Fig. 5. Sciatic nerve, 7 days after squalene administration. Well preserved neuronal fibers and Schwann cells (SC), bundles of small unmyelinated fibers (UF), lipid-like substance (LL) between myelin laminae and almost total destruction of myelin laminae with compressed axon by lipid-like products. X 8500.
Fig. 6. Sciatic nerve, 7 days after squalene administration. Blood vessels with narrowed lumen and hypertrophic endothelial cells (E). X 6300.
Exp Toxic Pathol51 (1999) 1
77
Fig. 7. Frontal cortex, 30 days after squalene administration. Dense lipid-like substance stored in neuron (N) and apoptosis of an endothelial cell in a blood vessel (V). X 12500.
Fig. 8. Cerebral white matter, 30 days after administration of squalene. Swollen astrocyte and astrocytic processes (A) and changed axons (Ax) with sparse myelin lamellae and segmental thinning and breakdown of myelin sheaths. X 12500. cerebral cortex and white matter, the hippocampus, and the sciatic nerve were harvested for electron microscopy. The samples were fixed in 4% glutaraldehyde in phosphate buffered saline (PBS), pH 7.4 for 2 h, washed in the same buffer for 1 h, postfixed with 1% osmium tetroxide for 1 h, washed in PBS for 2 h, and after dehydration in a gradient of ethanol and propylene oxide embedded in Epon 812. The blocks were cut with a LKB-Nova microtome and stained with uranyl acetate and Reynolds solution. The photographs were obtained in JEOL 1200 EX electron microscope.
Results The 7th day of the experiment Frontal cortex neurons were well preserved. Few mitochondria were swollen and a dilation of the Golgi complex and the rough endoplasmic reticulum were present. 78
Exp Toxic Pathol51 (1999) 1
A majority of the myelinated fibers in the cerebral grey and white matter demonstrated irregularities in the myelin lamellae structure (fig. 1). Very often the axons with lucent cytoplasm were compressed by oedematous fluid (fig. 1). Swelling of astrocytes and astrocytic processes was observed in the white matter of brain hemispheres and in the hippocampus, especially around the blood vessels (fig. 2). In the sciatic nerve the Schwann cells were swollen. There was a mild disintegration in the concentric myelin arrangement with formation of bizarre myelin figures (fig. 5.3,4). Between the myelin lamellae, the lipid-like deposits were seen and compression ofaxons by enormous amounts of lipid-like deposits was encountered (fig. 5). Many myelinated fibres demonstrated an almost total degeneration of the myelin lamellae. Non-myelinated fibers were normal. Some Schwann cells were swollen. The fibroblasts were activated and showed features of an augmented collagen production with an increased
Fig. 9. Hippocampus, 30 days after squalene injection. Hypertrophic endothelial cell (E) and narrow vessel lumen with red blood cell. X 18000.
Fig. 10. Sciatic nerve, 30 days after squalene administration. Very severe pathology of Schwann cells (SC) and degeneration of myelin forming onion-bulb formation (arrows). X 25000. amount of extracellular collagen fibrills in the perineurium. Hypertrophy of the endothelial cells and a constriction of vessels were noted, too (fig. 6).
The 30th day of the experiment Cortical and hippocampal neurons contained large lipid droplets in the cytoplasm (fig. 7). The myelin sheaths were disintegrated and the astrocytes were swollen, as seen at the 7th day of the experiment (fig. 8). In the cerebral hemispheres the endothelial cells were hypertrophic with a few cells showing typical features of apoptosis: chromatin aggregation, pyknosis, and cell shrinkage
(fig. 7). In the narrowed vessel lumen the aggregates of the morphological blood elements were encountered (fig. 9). In the sciatic nerve the Schwann cells contained an elevated number of cytoplasmic inclusions: dense bodies, multi lamellar inclusion bodies, lipid droplets, or empty vacuoles (fig. 10). This indicated an aberrant Schwann cell function in myelinogenesis. The myelin sheaths were abnormal showing ribbon-like widening of lamellae, onion-bulb formations, fusion, or delamination of myelin layers (fig. 10). Additionally, lipid droplets were present in the myelin sheaths. Activated macrophages with cytoplasmic lysosome-like inclusions or storage deposits were localized occasionally in this space. Exp Toxic Pathol51 (1999) 1
79
Discussion Our ultrastructural studies show that squalene produces pathological changes both in the CNS and the PNS. However, the magnitude of changes in the PNS was much higher than in the CNS. The changes in the CNS (astrocyte swelling, mild disturbances in the myelin sheaths) are relatively non-specific and found in other conditions such as cerebral ischemia or intoxication with various substances (MUDRICK and BAIMBRIDGE 1989; GAJKOWSKA et al. 1994; GAJKOWSKA et al. 1997). In the PNS (sciatic nerve) the main targets for squalene toxicity were myelin sheaths and the myelin-producing Schwann cells. As soon as 7 days after administration of squalene both disintegration of myelin sheaths and the swelling of Schwann cells were present. These disturbances were even more profound after 30 days when the ultrastructural alterations in Schwann cells (cytoplasmic inclusions) suggested a faulty myelination process. Squalene has been postulated to be responsible for encephaloneuropathy seen after tellurium administration. Our studies revealed some similarities in the neuropathological changes induced by those two agents. Both tellurium and squalene affect mostly PNS targeting Schwann cells and myelin sheaths. However, squalene produced some changes not normally seen after tellurium administration. Accumulation of lipid droplets in the myelin sheaths in PNS and in the neurons in the CNS were features characteristic for squalene. The mechanism of formation of lipid products is not known but may be simply related to the transport of the excess of squalene to the neural tissue. Alternatively, the lipid products may be formed due to metabolic disturbances caused by squalene. The changes in blood vessels and the increased collagen production in the PNS were also characteristic for squalene and those features have never been observed after tellurium intoxication. The hypertrophy of endothelium and a narrowing of vessel lumen may lead to tissue hypoperfusion and ischemia which can in tum aggravate the toxic effects of squalene. The increased synthesis of collagen may represent a reparative scarring in the sciatic nerve. In conclusion, the parenteral administration of squalene causes changes in the CNS and PNS, but does not reproduce the effects of tellurium exactly. Further investigations, e.g. the dose-response studies or the joint administration of squalene and tellurium must be performed to elucidate the relationships between tellurium and squalene in the development of encephaloneuropathy.
80
Exp Toxic Pathol51 (1999) 1
References 1. GAJKOWSKA B, GADAMSKI R, FRONTCZAK-BANIEWICZ
2.
3.
4. 5. 6. 7. 8.
M: Effects of staphylococcal a-toxin on the ultrastructure of the rat hypothalamo-neurohypophysial system. Acta Neurobiol Exp 1994; 54: 219-225. GAJKOWSKA B, FRONTCZAK-BANIEWICZ M, GADAMSKI R: Photochemically-induced vascular damage in brain cortex. Transmission and scanning electron microscopy study. Acta Neurobiol Exp 1997; 57: in press. HARRY GJ, GOODRUM JF, BOULDIN TW, et al.: Tellurium-induced neuropathology: metabolic alterations associated with demyelination and remyelination in rat sciatic nerve. J Neurochem 1989; 52: 938-945. LAMPERT P, GARRET RG: Mechanism of demyelination in tellurium neuropathy. Electron microscopic observations. Lab Invest 1971; 25: 380-388. LAMPERT P, GARRO F, PENTSCHEW A: Tellurium neuropathy. Acta Neuropathol (Berl.) 1970; 15: 308-317. MUDRICK LA, BAIMBRIDGE KG: Long-term structural changes in the rat hippocampal formation following cerebral ischemia. Brain Res 1989; 493: 179-184. RAWLINS FA, SMITH ME: Myelin synthesis in vitro: a comparative study of central and peripheral nervous tissue. J Neurochem 1971; 18: 1861-1870. SCHROEDER HA, BUCKMAN J, BALASSA J: Abnormal trace elements in man: tellurium. J Chron Dis 1967; 20:
147-161.
9. SMIALEK M, GAJKOWSKA B: Effects of sodium tellurite on the myelogenesis in the rat CNS. Acta Neurobiol Exp 1994; 54: 263. 10. SMIALEK M, GAJKOWSKA B, OTREBSKA D: Electron microscopy studies on the neurotoxic effect of sodium tellurite in the central nervous system of the adult rat. Brain Res 1994; 35: 223-232. 11. SMIALEK M, GAJKOWSKA B, PIOTROWSKI P, et al.: Experimental tellurium encephaloneuropathy in the rat. I. Effect of intoxication with sodium tellurite. Pol J Environmental Studies 1997; Suppl6: 189-191. 12. TAKAHASHI T: Experimental study on segmental demyelination in tellurite neuropathy. Hokkaido J Med Sci 1981; 56: 105-131. 13. WAGNER-RECIO M, TOEWS AD, MORELL P: Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination. J Neurochem 1991; 57: 1891-1901.
IThe Laboratory of the Ultrastructure of the Nervous System and 2Department of Neuropathology ,Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
The experimental squalene encephaloneuropathy in the rat B. GAJKOWSKA 1, M. SMIALEK2, R. P. OSTROWSKI2 , P. PIOTROWSKI 2 , and M. FRONTCZAK-BANIEWICZ 1 With 10 figures Received: August 6,1997; Revised: November 8,1997; Accepted: November 17,1997
Address for correspondence: BARBARA GAJKOWSKA, PhD, The Laboratory of the Ultrastructure of the Nervous System, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland; Fax: +48226685532. Key words: Squalene; Tellurium; Encephaloneuropathy; Endothelium; Astrocytes.
Summary
Introduction
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 ofaxons 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.
Squalene epoxydase (EC. 1. 1. 1.34 ) catalyzes the conversion of squalene (2,6,1O,15,23-hexamethyl-2,6,1O,14, 18,22-tracosohexaene) into 2,3-epoxysqualene. It has been postulated that squalene epoxydase is inhibited by tellurium (Te) and that an excess of squalene is responsible for a transient paralysis of the hind legs in weaning rats and a peripheral, segmental neuropathy after administration of tellurium (LAMPERT et al. 1970; HARRY et al. 1989; WAGNER-RECIO et al. 1991). Our electron microscopic studies showed a vulnerability of the myelinated fibers to tellurium, both in the maturing and in the mature rat brain and in the optic nerve (SMIALEK et al. 1994; SMIALEK and GAJKOWSKA 1994). The dynamics of the electron microscopic changes in the central nervous system (CNS) after tellurium intoxication showed a degeneration of myelin sheaths and myelin forming glia with a secondary axonal damage (SMIALEK et al. 1994). The pathomechanism of tellurium neurotoxicity in the CNS differs from that in the peripheral nervous system (PNS), where Schwann cell damage with secondary myeloclasis is present (TAKAHASHI 1981). The aim of this work was to evaluate the ultrastructural changes in the CNS and the PNS of adult rats following squalene administration and to compare them with the known features of tellurium encephaloneuropathy.
Material and methods Ten male rats (strain Wistar, weight approximately 150 g) were injected subcutaneously with liquid squalene (Sigma) once daily 20 g/kg of the body weight about 3 ml for 4 consecutive days. Five animals were used as controls. After 7 or 30 days from the initation of the experiment, the frontal Exp Toxic Patho151 (1999) 1
75
Fig. 1. A border of cerebral white and grey matter in the frontal lobe, 7 days after administration of squalene. Note swelling of mitochondria (M), dilation of some endoplasmic reticulum channels, and ultrastructurally changed myelinated fibers with compressed axons (Ax). X 12500.
Fig. 2. Hippocampus, 7 days after squalene injection. Swollen astrocytic processes (A) around blood vessel and hypertrophy of endothelial cells (E). X 8500.
Fig. 3. Sciatic nerve, 7 days after squalene injection. Mild ultrastructural changes in some myelinated fibers and an activated fibroblast (F). X 8500.
76
Exp Toxic Pathol51 (1999) 1
Fig. 4. Sciatic nerve, 7 days after squalene injection. Segmental disintegration of myelin laminae and formation of pathological myelin structures penetrating into the axon (Ax). X 12500.
Fig. 5. Sciatic nerve, 7 days after squalene administration. Well preserved neuronal fibers and Schwann cells (SC), bundles of small unmyelinated fibers (UF), lipid-like substance (LL) between myelin laminae and almost total destruction of myelin laminae with compressed axon by lipid-like products. X 8500.
Fig. 6. Sciatic nerve, 7 days after squalene administration. Blood vessels with narrowed lumen and hypertrophic endothelial cells (E). X 6300.
Exp Toxic Pathol51 (1999) 1
77
Fig. 7. Frontal cortex, 30 days after squalene administration. Dense lipid-like substance stored in neuron (N) and apoptosis of an endothelial cell in a blood vessel (V). X 12500.
Fig. 8. Cerebral white matter, 30 days after administration of squalene. Swollen astrocyte and astrocytic processes (A) and changed axons (Ax) with sparse myelin lamellae and segmental thinning and breakdown of myelin sheaths. X 12500. cerebral cortex and white matter, the hippocampus, and the sciatic nerve were harvested for electron microscopy. The samples were fixed in 4% glutaraldehyde in phosphate buffered saline (PBS), pH 7.4 for 2 h, washed in the same buffer for 1 h, postfixed with 1% osmium tetroxide for 1 h, washed in PBS for 2 h, and after dehydration in a gradient of ethanol and propylene oxide embedded in Epon 812. The blocks were cut with a LKB-Nova microtome and stained with uranyl acetate and Reynolds solution. The photographs were obtained in JEOL 1200 EX electron microscope.
Results The 7th day of the experiment Frontal cortex neurons were well preserved. Few mitochondria were swollen and a dilation of the Golgi complex and the rough endoplasmic reticulum were present. 78
Exp Toxic Pathol51 (1999) 1
A majority of the myelinated fibers in the cerebral grey and white matter demonstrated irregularities in the myelin lamellae structure (fig. 1). Very often the axons with lucent cytoplasm were compressed by oedematous fluid (fig. 1). Swelling of astrocytes and astrocytic processes was observed in the white matter of brain hemispheres and in the hippocampus, especially around the blood vessels (fig. 2). In the sciatic nerve the Schwann cells were swollen. There was a mild disintegration in the concentric myelin arrangement with formation of bizarre myelin figures (fig. 5.3,4). Between the myelin lamellae, the lipid-like deposits were seen and compression ofaxons by enormous amounts of lipid-like deposits was encountered (fig. 5). Many myelinated fibres demonstrated an almost total degeneration of the myelin lamellae. Non-myelinated fibers were normal. Some Schwann cells were swollen. The fibroblasts were activated and showed features of an augmented collagen production with an increased
Fig. 9. Hippocampus, 30 days after squalene injection. Hypertrophic endothelial cell (E) and narrow vessel lumen with red blood cell. X 18000.
Fig. 10. Sciatic nerve, 30 days after squalene administration. Very severe pathology of Schwann cells (SC) and degeneration of myelin forming onion-bulb formation (arrows). X 25000. amount of extracellular collagen fibrills in the perineurium. Hypertrophy of the endothelial cells and a constriction of vessels were noted, too (fig. 6).
The 30th day of the experiment Cortical and hippocampal neurons contained large lipid droplets in the cytoplasm (fig. 7). The myelin sheaths were disintegrated and the astrocytes were swollen, as seen at the 7th day of the experiment (fig. 8). In the cerebral hemispheres the endothelial cells were hypertrophic with a few cells showing typical features of apoptosis: chromatin aggregation, pyknosis, and cell shrinkage
(fig. 7). In the narrowed vessel lumen the aggregates of the morphological blood elements were encountered (fig. 9). In the sciatic nerve the Schwann cells contained an elevated number of cytoplasmic inclusions: dense bodies, multi lamellar inclusion bodies, lipid droplets, or empty vacuoles (fig. 10). This indicated an aberrant Schwann cell function in myelinogenesis. The myelin sheaths were abnormal showing ribbon-like widening of lamellae, onion-bulb formations, fusion, or delamination of myelin layers (fig. 10). Additionally, lipid droplets were present in the myelin sheaths. Activated macrophages with cytoplasmic lysosome-like inclusions or storage deposits were localized occasionally in this space. Exp Toxic Pathol51 (1999) 1
79
Discussion Our ultrastructural studies show that squalene produces pathological changes both in the CNS and the PNS. However, the magnitude of changes in the PNS was much higher than in the CNS. The changes in the CNS (astrocyte swelling, mild disturbances in the myelin sheaths) are relatively non-specific and found in other conditions such as cerebral ischemia or intoxication with various substances (MUDRICK and BAIMBRIDGE 1989; GAJKOWSKA et al. 1994; GAJKOWSKA et al. 1997). In the PNS (sciatic nerve) the main targets for squalene toxicity were myelin sheaths and the myelin-producing Schwann cells. As soon as 7 days after administration of squalene both disintegration of myelin sheaths and the swelling of Schwann cells were present. These disturbances were even more profound after 30 days when the ultrastructural alterations in Schwann cells (cytoplasmic inclusions) suggested a faulty myelination process. Squalene has been postulated to be responsible for encephaloneuropathy seen after tellurium administration. Our studies revealed some similarities in the neuropathological changes induced by those two agents. Both tellurium and squalene affect mostly PNS targeting Schwann cells and myelin sheaths. However, squalene produced some changes not normally seen after tellurium administration. Accumulation of lipid droplets in the myelin sheaths in PNS and in the neurons in the CNS were features characteristic for squalene. The mechanism of formation of lipid products is not known but may be simply related to the transport of the excess of squalene to the neural tissue. Alternatively, the lipid products may be formed due to metabolic disturbances caused by squalene. The changes in blood vessels and the increased collagen production in the PNS were also characteristic for squalene and those features have never been observed after tellurium intoxication. The hypertrophy of endothelium and a narrowing of vessel lumen may lead to tissue hypoperfusion and ischemia which can in tum aggravate the toxic effects of squalene. The increased synthesis of collagen may represent a reparative scarring in the sciatic nerve. In conclusion, the parenteral administration of squalene causes changes in the CNS and PNS, but does not reproduce the effects of tellurium exactly. Further investigations, e.g. the dose-response studies or the joint administration of squalene and tellurium must be performed to elucidate the relationships between tellurium and squalene in the development of encephaloneuropathy.
80
Exp Toxic Pathol51 (1999) 1
References 1. GAJKOWSKA B, GADAMSKI R, FRONTCZAK-BANIEWICZ
2.
3.
4. 5. 6. 7. 8.
M: Effects of staphylococcal a-toxin on the ultrastructure of the rat hypothalamo-neurohypophysial system. Acta Neurobiol Exp 1994; 54: 219-225. GAJKOWSKA B, FRONTCZAK-BANIEWICZ M, GADAMSKI R: Photochemically-induced vascular damage in brain cortex. Transmission and scanning electron microscopy study. Acta Neurobiol Exp 1997; 57: in press. HARRY GJ, GOODRUM JF, BOULDIN TW, et al.: Tellurium-induced neuropathology: metabolic alterations associated with demyelination and remyelination in rat sciatic nerve. J Neurochem 1989; 52: 938-945. LAMPERT P, GARRET RG: Mechanism of demyelination in tellurium neuropathy. Electron microscopic observations. Lab Invest 1971; 25: 380-388. LAMPERT P, GARRO F, PENTSCHEW A: Tellurium neuropathy. Acta Neuropathol (Berl.) 1970; 15: 308-317. MUDRICK LA, BAIMBRIDGE KG: Long-term structural changes in the rat hippocampal formation following cerebral ischemia. Brain Res 1989; 493: 179-184. RAWLINS FA, SMITH ME: Myelin synthesis in vitro: a comparative study of central and peripheral nervous tissue. J Neurochem 1971; 18: 1861-1870. SCHROEDER HA, BUCKMAN J, BALASSA J: Abnormal trace elements in man: tellurium. J Chron Dis 1967; 20:
147-161.
9. SMIALEK M, GAJKOWSKA B: Effects of sodium tellurite on the myelogenesis in the rat CNS. Acta Neurobiol Exp 1994; 54: 263. 10. SMIALEK M, GAJKOWSKA B, OTREBSKA D: Electron microscopy studies on the neurotoxic effect of sodium tellurite in the central nervous system of the adult rat. Brain Res 1994; 35: 223-232. 11. SMIALEK M, GAJKOWSKA B, PIOTROWSKI P, et al.: Experimental tellurium encephaloneuropathy in the rat. I. Effect of intoxication with sodium tellurite. Pol J Environmental Studies 1997; Suppl6: 189-191. 12. TAKAHASHI T: Experimental study on segmental demyelination in tellurite neuropathy. Hokkaido J Med Sci 1981; 56: 105-131. 13. WAGNER-RECIO M, TOEWS AD, MORELL P: Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination. J Neurochem 1991; 57: 1891-1901.