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Histopathological changes induced by intrahippocampal injections of low doses of kainic acid (17.5 ng/site) were investigated in rats. Kainic acid produced a selective loss of CA3 pyramidal and hilar neurons. The development of kainic acid-induced neuronal injury was not accompanied by any detectable loss of histologically demonstrable zinc as assessed by means of a modified Timm's sulphide-silver method. It is suggested that the selective injury of hippocampal neurons induced by kainic acid is not contingent on the release of zinc from mossy-fiber terminals.

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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.

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Apolipoprotein E (apo E) is synthesized and released in greatly increased amounts by peripheral nerve following Wallerian degeneration; it has been suggested that this protein may function in the transport of degenerated myelin lipid. The purpose of this study was to determine if the amount of apo E released by rat peripheral nerve is increased following selective demyelination, in the absence of significant axonopathy. Using an immunoturbidimetric assay, release of apo E from excised sciatic nerve segments was measured during the phases of acute demyelination and remyelination caused by tellurium (Te) toxicity, during segmental demyelination in chronic lead (Pb) poisoning, and during Wallerian degeneration following nerve crush. Morphologic changes were examined in contralateral sciatic nerves by nerve-fiber teasing or by light and electron microscopy of transverse sections. As in previous studies, the amount of apo E released from the nerves was greatly increased following Wallerian degeneration due to nerve crush. In Te neuropathy, increased release of apo E was first detected on the fourth day of Te exposure, corresponding temporally to the acute onset of paralysis and segmental demyelination. Apolipoprotein E release rose steeply to a maximum of ten times the control values by day 9 and then gradually waned during the next five weeks, corresponding to a period of active remyelination and resolution of the neuropathy. In the demyelinating neuropathy of chronic lead poisoning, apo E release was increased four times over control animals after seven weeks of exposure, with less than 10% of teased fibers showing early paranodal demyelination and no evidence of remyelination.(ABSTRACT TRUNCATED AT 250 WORDS)

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In 81 patients with anaplastic supratentorial gliomas, single versus multiple chemotherapeutic agents were selected for treatment following surgery and during radiotherapy in a prospective randomized study. Time to treatment failure and survival were not significantly enhanced by multiple agent chemotherapy, as administered in this study.

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Previous studies have demonstrated that at day 7 following treatment, administration of 3 or 7 mg/kg trimethyltin (TMT) to male Long-Evans rats caused decreases in the concentrations of DA in nucleus accumbens, and perturbed serotonergic function in regions of brain that receive serotonergic innervation from the raphe nuclei. The present series of experiments extended these observations by examining the time course of these events from 14 to 28 days after treatment. Following a dose of 7 mg/kg, changes in serotonergic function, as evidenced by increased turnover and decreased concentrations of 5-HT, were present in striatum, olfactory tubercle, septum and frontal cortex. In nucleus accumbens, concentrations of DA were decreased up to 21 days, while in frontal cortex concentrations of DOPAC and HVA were elevated only at 14 days. In concert with our previous studies, these data indicate that administration of TMT continues to affect serotonergic systems up to 28 days, and dopaminergic systems up to 21 days after exposure, with striatum, nucleus accumbens, olfactory tubercle and septum exhibiting persistent effects due to administration of this neurotoxicant. These prolonged alterations in serotonergic function suggest that this system may play an important role in the response to intoxication with TMT.

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The prevalence of demyelinated fibers in mixed nerve (sciatic) and cutaneous nerve (sural) and the change in lead levels in various tissues over time were assessed in a model of lead neuropathy in the rat. Long-Evans rats were given drinking water containing 4% lead acetate and killed between one and 213 days of exposure. Lead levels in blood, brain, kidney, and femur increased over the 213-day period. Lead levels in sciatic nerve appeared to increase rapidly during the first few weeks of exposure and then decline to a lower plateau. The neuropathy was characterized by segmental demyelination and remyelination; neither axonal degeneration nor a microangiopathy was found. Sciatic nerve had a significantly greater prevalence of demyelinated fibers than sural nerve; the prevalence of demyelinated fibers was similar in proximal and distal sciatic nerve. The variable, brain-lead concentration times days on lead, which is an indicator of cumulative brain exposure, was the best predictor of the prevalence of demyelination. The differential involvement of sciatic and sural nerves in lead neuropathy may either indicate that Schwann cells myelinating different nerve-fiber populations have different susceptibilities to lead toxicity, or that lead preferentially enters sciatic nerve.

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During a defined postnatal developmental period, the 2nd through the 28th postnatal day, rats were exposed daily to either an oral administration of 200 mg lead (as lead acetate) per kilogram of body weight, an 8-hr maternal milk deprivation schedule, or a combination of the two insults. On the 29th day the rats were killed. Either lead exposure or milk deprivation alone decreased brain (10%) and body (15%) weights, and an additive effect was observed in rats exposed to both lead and milk deprivation (brain: 20%; body: 35%). Neither the lead nor the deprivation insult alone produced a perturbation in the process of myelination. However, when the two conditions were combined an interaction was evident as a 25% decrease in myelin accumulation in females. No effect was seen in males. The myelination deficit in females was specific in that neither accumulation of glial fibrillary acidic protein (a marker for astroglial cells) nor neurofilament protein (a marker for neurons, especially axons) was perturbed. Tissue lead concentrations did not suggest that this increased sensitivity in females was due to a selective increase in their body burden of lead.

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The content of Synapsin I (Protein I) was examined in brain regions of adult rats exposed to trimethyltin (TMT), and in control animals. Long Evans hooded rats were intragastrically dosed with 4 mg TMT hydroxide/kg body weight for 4 days. No perturbations in Synapsin I levels were evident by 24 h following the fourth dose; however, by 36 h, a significant decrease of 28% in Synapsin I level was present in the hippocampus of TMT treated animals. This decrease was selective, no other brain region examined was affected. As determined by regional analysis of inorganic tin, this specificity was not due to a profound preferential accumulation of tin in the hippocampus. Despite the absence of an alteration in Synapsin I levels at 24 h, morphological examination revealed perturbation in the normal uniform arrangement of granule cell neurons, with dead neurons diffusely distributed throughout the facia dentata. At 36 h, these changes were only slightly more extensive. In contrast, examination of the terminal projection area of these cells, the mossy boutons, showed to be unaffected at 24 h after the 4th dose of TMT. However, by 36 h, many of the mossy boutons contained dense bodies and showed signs of degeneration. This result suggested that the loss of Synapsin I coincides with degeneration of the nerve terminal region. In order to better establish the temporal correlation, a less severe dosing regimen (only 3 days of exposure to 4 mg TMT/kg body wt) was utilized to attenuate the time course of necrosis. Again, necrotic changes were visible in the perikaryon by 1 day after termination of toxicant dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

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Previous studies have demonstrated that postnatal (days 2-29 of life) administration of lead (200 mg/kg/day by gavage) to Long-Evans rats caused permanent increases in lithium-induced polydipsia (LIP). These lead-induced increases in LIP were apparently not of renal origin, did not occur in animals treated with lead after day 30, and persisted for at least 6 months. The present studies have narrowed the dose-time window for lead-induced increases in LIP. The first study showed that continuous administration of lead (200 mg/kg/day, p.o.) in the form of lead acetate during days 2-9 of life caused increases in LIP (P = 0.022). Although lead-induced increases in LIP were not statistically significant (P = 0.084) for the group administered lead from days 9 to 19, the lack of a significant difference between the 2-9- and 9-19-day groups suggested that lead treatment during either of these time periods would result in LIP increases. Lead administration between days 19 and 29 of life was not effective in increasing LIP (P = 0.8). In the second study, a single dose of lead (200 mg/kg/day) was administered either on day 5 or 15 of life. Concentrations of lead in the blood on day 30 of life averaged 23.2 micrograms/100 ml for treated rats versus 4.8 micrograms/100 ml for controls. When tested at approximately 90 days of age, both groups showed significant increases in LIP (P = 0.028). The rats from this second study were also examined for changes in nigrostriatal dopamine function, since this pathway is known to be essential for LIP.(ABSTRACT TRUNCATED AT 250 WORDS)

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Retinal neurons from rats acutely intoxicated with trimethyltin (TMT) were examined by light and electron microscopy to determine if there is a relationship between the subcellular response of a neuron to TMT and its morphologic subspecialization. Subcellular pathologic alterations were present in neurons from all three cellular layers of the sensory retina. However, the type and degree of subcellular response varied among the highly subspecialized neurons of the different retinal layers. Clusters of dense-cored vesicles and tubules were mainly limited to neurons of the ganglion-cell layer, large accumulations of dense bodies were mainly limited to neurons of the inner nuclear layer, and neuronal necrosis was mainly limited to the photoreceptor cells. The inner segment of the photoreceptor cell shared with the perikaryon of more conventional neurons a special vulnerability to TMT cytotoxicity. Our results suggest that the morphologic subspecialization of neurons affects the type and the degree of subcellular response to TMT.

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The toxicology of tin is almost entirely the toxicology of the organic compounds of tin, for the metal itself and its inorganic compounds appear to be nearly harmless for practical purposes. Furthermore, the neurotoxicity of organotin is essentially that of trimethyltin and triethyltin.

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Administration of trimethyltin (TMT) or triethyltin (TET) compounds to rats during postnatal development has known behavioral and neuropathological consequences. By measuring the concentrations of dopamine, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid, gamma-aminobutyric acid, acetylcholine, and choline in different brain areas of TMT and TET-treated animals, an attempt was made to correlate these functional deficits with changes in CNS neurotransmitter alterations in vivo. TET had no effect on any of the substances measured whereas TMT significantly decreased gamma-aminobutyric acid and dopamine levels, but only in hippocampus and striatum, respectively. All other neurotransmitter substances measured were not affected. These findings illustrate the complexity inherent in attempting to use neurochemical techniques alone as an index of toxicity in the absence of specific defined hypotheses.

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The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.

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The effect of the structure of organotin compounds on their toxicity and neurotoxicity to the developing rat has been studied. Oral administration was used after selection of a vehicle that gave uniform organotin solubilization as evidenced by toxicity and chemical solubility data. This vehicle was milk plus Tween-80. Eight different organotin compounds were systematically surveyed for effects in the neonatal rat. Trimethyl- and triethyltin were most toxic, and were somewhat more toxic than tri-n-propyltin. Tri-n-butyltin was somewhat less toxic, while tricyclohexyl-, triphenyl-, diethyl- and dimethyltin were least toxic. Some higher doses of trimethyl- or triethyltin caused neuropathological changes that were characteristic for each compound, these changes being absent for the other agents. Regardless of their toxicity, significant amounts of tin, as the element, were found in brain, kidney, and liver after treatment with all agents. However, detectable blood values were only obtained for trimethyl- and triethyltin.

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Long-Evans rats were intubated with 0.3 or 1.0 mg/kg of triethyltin sulfate (TET) or 0.3 mg/kg of trimethyltin hydroxide (TMT) from postnatal day 3-29. 1.0 mg/kg of TMT was given on alternate days beginning on postnatal day 3. Learning and memory were assessed in an automated radial-arm maze when the rats were 180-200 days old. With this maze accuracy and activity data can be collected simultaneously. TET or TMT treatment resulted in an increase in the number of days required to adequately perform and radial-arm maze task, and a transient deficit in accuracy. However, the most pronounced effect in both TET and TMT-treated animals was hyperactivity which became manifest on the second day of testing and persisted throughout the remainder of testing.

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Specific immunofluorescent techniques were utilized to demonstrate the regulatory (RI and RII) and catalytic (C) subunits of cyclic AMP-dependent protein kinase, and calmodulin, in the rat cerebellar Purkinje cell during post-natal ontogenesis. Whereas these second messenger receptor proteins were not detectable at 5 days, an increase in staining intensity occurred from this time until adult levels and distribution were attained at 25 days. Differences in immunofluorescent staining were noted between these proteins during ontogenesis. The relationship of these immunocytochemical changes to synaptogenesis and cellular maturation are discussed, including possible interactions between cyclic AMP and calcium messenger systems.

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