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PubMed1986

The relation of the neurotoxicity of organic tin and lead compounds to neurotubule disaggregation.

The effect of organic lead and tin compounds upon the integrity of cerebral neurotubules has been studies in vitro and in vivo, using 3H-colchicine binding as an index of tubulin aggregation. Triethyl tin, trimethyl lead and triethyl lead chlorides at concentrations above 5 X 10(-5)M, all prevented the polymerization of tubulin. Inorganic lead had a similar effect. Trimethyl tin had a much lesser capacity to prevent such polymerization. Rats received a single dose of each organometal, by subcutaneous injection and the capacity of hippocampal soluble protein to bind 3H colchicine was assessed. At organometal doses sufficient to cause morphological damage and behavioral change, no significant differences of colchicine binding capacity were apparent.

Animals↗
PubMed1984

Developmental neuropathology of organotin compounds.

The literature concerning the developmental neuropathology of organotins is reviewed. To date, neuropathological effects have been convincingly demonstrated for trimethyltin (TMT) and triethyltin (TET). Both compounds may damage the developing CNS; however they have different cellular targets. TMT is a neuronotoxin which damages areas of the limbic system, cerebral cortex, and brainstem. TET is a myelinotoxin which causes massive myelinic edema by yet undetermined mechanisms. Neuronal death is also seen following TET intoxication during the neonatal period, possibly as a result of elevated intracranial pressure. The neuropathological features of TMT and TET intoxication during early life are presented. Neurochemical and behavioral alterations resulting from congenital and/or neonatal exposure to organotins are also discussed.

Animals↗
PubMed1984

Organometal-induced antinociception: a time- and dose-response comparison of triethyl and trimethyl lead and tin.

Recent reports have demonstrated that organolead and -tin compounds can alter behavioral reactivity to noxious stimuli. To further define the dose response and temporal characteristics of these neurobehavioral effects, male Fischer 344 rats were injected sc with either one-fourth, one-half, or three-fourths the acute LD50 of triethyl lead (TEL), triethyl tin (TET), trimethyl lead (TML), trimethyl tin (TMT), or distilled water and tested on a 57.5 degrees C hot plate 1, 7, 14, 21, and 28 days after dosing. All four organometals altered hot plate latencies, but the magnitude and time course of these effects differed among the compounds. TEL produced a dose-related increase in latencies which was maximal 1 and 7 days postdosing and had dissipated by 28 days. In contrast, the group administered TML (3/4 LD50) exhibited a late developing antinocioception which became evident 14 days after dosing and persisted throughout the period of testing. The intermediate dose of TMT (1/2 LD50) also produced a delayed increase in response times which was observed 21 and 28 days post-treatment. The 3/4 LD50 dose of TMT produced increased hot plate latencies on all post-treatment test days except Day 14. TET (1/2 LD50) produced increased hot plate latencies 1, 7, 14, and 21 days postdosing and also induced a reversible ataxia and akinesia. Higher doses of TET proved lethal to 80% of the animals and lower doses failed to alter response times in the hot plate. These data demonstrate that trialkyl lead and tin compounds can produce time- and dose-related increases in hot plate latencies.

Animals↗
PubMed1986

[Mechanism of action of Ginkgo biloba extract in experimental cerebral edema].

Oedema is one of the major complication of cerebral ischaemia being at the same time a consequence and an aggravating factor. Its first phase is intracellular and cytotoxic, with breakdown of ionic pumps through loss of energy, resulting in a whole sequence of ionic perturbations characterized by loss of intracellular K+ and accumulation of water and Na+, Cl-, and Ca2+ ions in the cells of the ischaemic zone. The second phase, termed vasogenic, applies to the accumulation of lactates, inorganic phosphates and free polyunsaturated fatty acids and in particular, arachidonic acid. This last compound is responsible for the production of membrane "aggressors", amongst which free radicals play an important rôle. Ginkgo biloba extract limits the formation of cerebral oedema and suppresses its neurological consequences, whether the oedema is of cytotoxic (triethyltin) or vasogenic (unilateral traumatic oedema) origin. Several membrane mechanisms could be implicated in the protective action manifested by Ginkgo biloba extract against cerebral oedema.

Animals↗
PubMed1991

Resonance ionization spectroscopy for multiplex sequencing of tin-labeled DNA.

A method is described for synthesis of a tin reagent, triethylstannylpropanoic acid (TESPA), and its attachment to oligonucleotide primers. Except for the expected mobility retardation, the presence of [116Sn]-TESPA did not affect the sequencing ladder on electrophoresis gels. By using [120Sn]-TESPA and [35S]-dTTP simultaneously in the Sanger procedure, DNA bands on an electrophoresis gel were first located by autoradiography and then by resonance ionization spectroscopy to demonstrate the coincidence of the signals. Previous results using stable isotopes as labels on model compounds are now confirmed by their use in actual DNA sequencing products.

Autoradiography↗
PubMed2001

Toxicity of organotin compounds in primary cultures of rat cortical astrocytes.

The neurotoxic organotin compounds trimethyl (TMT) and triethyltin (TET) are known to induce astrogliosis in vivo, which is indicated by an increased synthesis of glial fibrillary acidic protein (GFAP) in astrocytes. In contrast, tributyltin (TBT) does not induce astrogliosis. The aim of this study was to investigate whether trialkyltin derivatives can induce an increased GFAP synthesis in astrocyte cultures in the absence of neurons and whether differences between the action of TMT, TET, and TBT can be detected. Primary cultures of rat cortical astrocytes from 2-day-old rats were grown in 96-well plates until confluency and then exposed to various concentrations of TMT, TET, and TBT for 40 h. Effects on basal cell functions were measured by colorimetric determination of cell protein contents and by assessment of viability by means of the MTT assay. An indirect sandwich ELISA for 96-well plates was used for quantitative measurements of the GFAP content of the cells. All three compounds induced a concentration-dependent cytotoxicity indicated by parallel decreases of protein contents and MTT reduction. Half-maximum cytotoxic concentrations were 3 micromol/L (TBT), 30 micromol/L (TET), and 800 micromol/L (TMT). Cellular GFAP contents were reduced in parallel to cytotoxic action but no increase in GFAP expression at subcytotoxic concentrations could be observed. Thus, the astrocytes were not able to respond to TMT or TET exposure by an increased synthesis of GFAP in the absence of neuronal signals.

Animals↗
PubMed1984

The response of oligodendrocytes to chemical injury.

Oligodendrocytes establish relationships with axons at myelination which commit the cell to make and then maintain certain volumes of myelin. As a result of this oligodendrocytes are a heterogenous population of cells. At one extreme, large cells support a single internode on large diameter axons while at the other, small cells support many internodes on small diameter axons. Although it is common practice to separate chemicals which cause vacuolation of myelin sheaths from those which bring about cell death and thus demyelination, many compounds produce vacuolation and/or cell degeneration depending on concentration; an observation which suggests that myelin sheath-associated vacuolation reflects oligodendrocyte toxicity rather than a specific myelinopathy. The restoration of myelin sheath-axon relationships following chemically induced demyelination requires a complex sequence of cell-cell interactions to occur in an orderly manner if new myelin sheaths are to be formed. Recruitment of new oligodendrocytes can be separated from the interaction of oligodendrocytes with axons which results in the laying down of a myelin sheath. The latter event can only take place in the absence of demyelinating agents and in the presence of astrocytes.

6-Aminonicotinamide↗
PubMed1975

Water in brain edema. Observations by the pulsed nuclear magnetic resonance technique.

The state of water in three types of brain edema and in normal brain of the rat was studied by the pulsed nuclear magnetic resonance (NMR) technique. In cold-induced edema and in osmotic edema both in cortex and in white matter, the water protons have longer nuclear magnetic relaxation times than in normal brain. The observed changes correlate with the water content of the brain tissue. In triethyltin induced edema, no change was found for relaxation times in the cortex, whereas in the white matter, an additional fraction was observed with much longer relaxation times, attributable to fluid within the vesicles in the myelin sheaths. Since the NMR technique is non-destructive, it is potentially applicable in the living patient as a method for the detection of brain lesions that are accompanied with changes of brain water.

Animals↗
PubMed2004

Triethyltin-induced stress responses and apoptotic cell death in cultured oligodendrocytes.

Triethyltin (TET)-induced neurotoxicity in the brain causes the formation of myelin edema and loss. Myelin deficits produced by early postnatal exposure to TET are permanent and cannot be repaired as the brain matures. The underlying causes have not been resolved. To investigate whether TET directly affects oligodendrocytes, the myelin-forming cells of the central nervous system, cultured rat brain oligodendrocytes were prepared and treated with TET. The data show that TET was cytotoxic for oligodendrocytes and led to the onset of programmed cell death, as indicated by DNA fragmentation. Cellular membranous extensions were severely damaged, and the nuclei appeared to be condensed and fragmented. Concomitantly, the small heat shock protein HSP32, also known as heme oxygenase-1 (HO-1), and an indicator of oxidative stress, as well as the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2), were observed. ERK1,2 have been implicated to participate in the regulation of cell death and survival. Myelin-specific proteins MBP and CNP were not affected. In TET-treated cells mitochondria redistributed from the processes to the cell somata near the nucleus, possibly as a consequence of microtubule disorganization. A disturbance of the mitochondrial membrane potential and mitochondrial fragmentation occurred. Hence, it might be hypothesized that oligodendroglial PCD, rather than axonal degeneration, contributes to myelin damage and deficits observed in rats after treatment with TET in vivo.

Animals↗
PubMedDate not supplied

Discrimination between different types of white matter edema with diffusion-weighted MR imaging.

Brain edema can be classified into three categories: vasogenic, cytotoxic, and interstitial. The mechanism of edema is thought to be different in each type. The authors studied the movement of water molecules in each type of white matter edema in a rat model by using diffusion-weighted magnetic resonance imaging. Conventional T2-weighted imaging did not allow distinction between the three types of white matter edema; the three types of edema were, however, distinguished by using diffusion-weighted imaging. The apparent diffusion coefficient (ADC) of water was different in each type of edema. Water molecules in cytotoxic edema induced by triethyl-tin intoxication showed a smaller and less anisotropic ADC than in normal white matter. In contrast, water in vasogenic edema induced by cold injury had a larger and more anisotropic ADC than in normal white matter. Water in interstitial edema due to kaolin-induced hydrocephalus had an anisotropic and very large ADC.

Animals↗
PubMed1993

Identification of membrane-bound carbonic anhydrase in white matter coated vesicles: the fate of carbonic anhydrase and other white matter coated vesicle proteins in triethyl tin-induced leukoencephalopathy.

We have extended our studies on the content of white matter derived coated vesicles (WMCVs) to show that they are enriched in membrane-bound carbonic anhydrase. Within the myelin complex membrane-bound carbonic anhydrase is concentrated in the periaxolemmal domain; however, this protein is enriched almost sevenfold in the bilayer of coated vesicles even relative to this myelin membrane region. These data suggest that some vesicles are derived from a site at which this enzyme is highly localized. The enrichment observed for membrane-bound carbonic anhydrase is unique since other periaxolemmal proteins such as CNPase and plasmolipin are only present in equal amounts in periaxolemmal-myelin fractions and WMCVs. Based on their known localization, the presence of CNPase coupled with the absence of MAG in WMCVs suggest that these vesicles are derived from the paranodal region. The identification in WMCVs of periaxolemmal-myelin proteins associated with ion and fluid movement, such as carbonic anhydrase, Na+,K+ ATPase, and the putative K+ channel protein plasmolipin, prompted us to examine the status of these vesicles in triethyl tin (TET)-induced myelin edema. Coated vesicles and other membrane fractions were isolated from whole brains of control and TET-treated rats. Whole brains were used so we could compare the effects of TET on WMCV proteins with the effect on proteins enriched in gray matter coated vesicles. The results indicated that TET had no detectable effect on compact or periaxolemmal-myelin, however, Western blot analysis showed that WMCV proteins, such as carbonic anhydrase, CNPase, and plasmolipin, were virtually absent or greatly diminished from the whole brain coated vesicle fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

In vitro organotin administration alters guinea pig cochlear outer hair cell shape and viability.

Trimethyltin (TMT) and triethyltin (TET) disrupt auditory function at doses far below those shown to be neurotoxic. In vivo studies suggest that the initial effect of TMT on hearing occurs at the inner hair cell/spiral ganglion cell synapse, while later, the outer hair cell (OHC) undergoes structural and functional damage. TET produces acute effects upon afferent neurotransmission similar to those observed following TMT, but TET's effects on OHC structure and function have not been examined. OHCs are motile elements within the cochlea, believed to modulate the sensitivity and tuning within the inner ear. Changes in OHC length may alter hearing function, and length changes have been reported following exposure to various ototoxic agents in vitro. In the present study, 77 OHCs from 45 pigmented male guinea pigs were isolated in primary culture and exposed for 90 min to concentrations between 30 microM and 1.0 mM of TMT or TET and then to bathing medium for 30 min to remove the toxicant. Significant shortening of the OHC cell body occurred at all doses to both organotins, with a mean reduction in length of 15.1 and 20.2% for 1.0 mM TMT and TET, respectively, at the end of testing; control cells were only 3.4% shorter at the end of 90 min of perfusion with bathing medium. The effect of organotin exposure on OHC volume was not consistently related to either TMT or TET concentration or altered cell length. In addition, disruption of the plasma membrane characterized by bleb formation, the forceful ejection of cytoplasm, or bursting was seen in 80% of cells exposed to 1.0 mM TET, although not TMT; lower concentrations of both organotins disrupted the cell membrane in 10-30% of cells. Membrane rupture was not reliably associated with either increased cell volume or decreased length, implicating a weakening of the plasma membrane or cortical lattice as the basis for this effect. Consistent with the irreversible structural weakening of the lateral wall, resorption of organotin-induced cytoplasmic blebs was never evidenced. Qualitatively, subcellular elements in the central core of many organotin-treated OHCs appeared pathological. These changes are similar to histopathological changes observed following in vivo organotin administration and may represent one target of acute alkyltin ototoxicity.

Animals↗
PubMed1996

Triethyltin interferes with Ca2+ signaling and potentiates norepinephrine release in PC12 cells.

We have investigated the effects of triethyltin (TET) on agonist-stimulated Ca2+ signaling and neurosecretion in PC12 cells. Treatment of PC12 cells with 10 microM TET elicited a slow increase of the resting cytosolic free Ca2+ concentration due to Ca2+ release from intracellular stores. Furthermore, TET modified the Ca2+ responses elicited by bradykinin (Bk), adenosine triphosphate (ATP), or high K+. TET potentiated the peak Ca2+ response stimulated by Bk in both the presence and the absence of extracellular Ca2+, and prolonged the recovery phase after ATP stimulation. In contrast, the Ca2+ transient elicited by bathing cells in high K+ was markedly reduced, suggesting that TET can differentially affect several targets on Ca2+-signaling pathways. Neurotransmitter depletion follows in vivo exposure to TET. Since neurotransmitter secretion is strictly dependent on intracellular Ca2+ signals we also investigated whether treatment with TET modified norepinephrine release from PC12 cells. TET did not elicit norepinephrine release, but it enhanced the release of norepinephrine induced by Bk or ATP. The increased release of norepinephrine elicited in combination with Bk was independent from extracellular Ca2+. Our results suggest that possible neurotoxic effects of TET can derive from its ability to modulate Ca2+ signaling and eventually neurosecretion.

Animals↗
PubMed1990

MR studies of brain oedema in the developing animal.

Assessment of perinatal brain oedema is complicated by normal changes in brain water that accompany the marked physiological, biochemical and morphological alterations occurring during this phase of development. Multiexponential analysis of transverse decay curves (TDCs), derived from 128 echo CPMG images, of white matter (WM) made oedematous by either exposure of animals to triethyltin (TET) or cryogenic cortical lesions revealed a second, slower decay component not apparent in controls. More significantly, an obvious difference was noted between the TET and cryogenic lesion fast decay components which might serve as a basis to differentiate non-invasively cytotoxic and vasogenic oedemas.

Aging↗
PubMed1976

Some physiological alteration associated with pleiotropic cross resistance and collateral sensitivity in Saccharomyces cerevisiae.

A mutant strain (2-20) isolated by growth on medium containing oligomycin and cycloheximide was also found to be cross resistant to antimyicn, cerulenin, chloramphenicol, tetracycline, triethyltin and triphenylmethylphosphonium bromide, but collaterally sensitive to dequalinium chloride, gentamycin, neomycin, paromomycin and thiolutin. Growth of 2-20, compared to the parental strain and 2 complete revertants, under a variety of environmental conditions revealed that strain 2-20 had an enhanced sensitivity to increased osmolality, elevated pH, and high temperature; in addition, strain 2-20 was unable to polymerize aminoimidazole ribotide at 37 degrees C as shown by the failure to develop a red colony in the presence of ade 2. Four complex solid media (glucose--KCI, galactose, ethanol, ethanol--KCI, Table 1) unable to sustain the growth of strain 2-20 were arbitrarily chosen to monitor cellular growth under different physiological conditions. Tetrad analysis indicated that the complex phenotype (cross resistance, collateral sensitivity, inablity to polymerize aminoimidazole ribotide, absence of growth under adverse physiological conditions) was inherited by an allele of a locus previously shown to result in a permeability barrier of the plasma membrane to chloramphenicol. 582 of 640 subclones used to isolate revertants of 2-20, under four different physiological conditions, were observed to produce a complete revertant of the complex phenotype. It is proposed that the pleiotropic phenotype could result from an alteration of the plasma membrane and mitochondrial inner membrane by a single nuclear gene mutation.

Alleles↗
PubMed1982

Measurement of edema in the nervous system. Use of Percoll density gradients for determination of specific gravity in cerebral cortex and white matter under normal conditions and in experimental cytotoxic brain edema.

A method is presented by which density measurements can be performed on samples from cerebral cortex and white matter of normal and intoxicated animals using nontoxic ingredients as an alternative to the bromobenzene-kerosene technique described by Nelson et al. (1971). A continuous density gradient is prepared in a calibrated glass cylinder by using a new product, Percoll, which consists of colloidal silica particles coated with polyvinyl pyrrolidone. The gradient is stable and the same column can be used for repeated experiments over a long period of time. Interactions between the gradient media and the samples are evaluated and various methodological aspects concerning removal and handling of the tissue samples are presented. Experiments with acute triethyltin (TET) intoxication in the mouse and the hamster show that the Percoll technique can be used as an alternative to the bromobenzene-kerosene method in quantitative studies on cytotoxic brain edema.

Animals↗