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Results for “Trimethyltin Compounds”

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PubMed1994

Selective loss of the 180-kDa form of the neural cell adhesion molecule in hippocampus and cerebellum of the adult mouse following trimethyltin administration.

The neural cell adhesion molecule (NCAM), a membrane glycoprotein which plays critical roles in cell-cell recognition and in the maintenance of cytoarchitecture in the adult brain, may be modulated in response to injury. To determine whether neurotoxic insult alters the profile of NCAM expression, adult female Balb/c mice were given a single injection of trimethyltin chloride (TMT; 3.2 mg/kg ip) and killed 4 hr to 3 weeks later. Hippocampus and cerebellum were isolated and prepared for light microscopy or SDS-PAGE and immunoblot analysis using the monoclonal antibody 5B8, which recognizes the intracellular domains of the 140- and 180-kDa isoforms of NCAM. NCAM140 appeared unaffected in TMT-treated mice at all time points. In contrast, decreased intensity of the 180-kDa band was apparent in both hippocampus and cerebellum 4 hr after TMT administration; maximal loss of NCAM180 was seen in hippocampal immunoblots 8 to 64 hr after treatment. The decrease in NCAM180 followed a similar but less pronounced course in cerebellum. Recovery of the 180-kDa band in hippocampus and cerebellum was apparent around 64 hr and continued until NCAM180 of mice killed 3 weeks after treatment resembled that of controls. No change in glial fibrillary acidic protein was seen by immunoblot analysis, suggesting that the effect is selective for neurons. TMT-induced loss of NCAM180 may be a direct cytotoxic effect, or may represent a reactive neuronal response to injurious stimuli. In either case, loss of NCAM180 accompanies cell injury following toxicant exposure and may be related to cytoskeletal alterations and destabilization of cellular contacts.

Animals↗

PubMed2001

Trimethyltin-activated cyclooxygenase stimulates tumor necrosis factor-alpha release from glial cells through reactive oxygen species.

Exposure of a primary culture of glial cells to the classical neurotoxicant trimethyltin (TMT) results in the release of prostaglandin (PG)E(2) and tumor necrosis factor (TNF)-alpha. Prior treatment of glial cells with either the nonspecific inhibitor of cyclooxygenase and lypoxygenase eicosatetraynoic acid (ETYA) or the cyclooxygenase inhibitor indomethacin completely prevented TMT-induced PGE(2) production and TNF-alpha release, suggesting a role for cyclooxygenase metabolites in TMT-induced TNF-alpha release. Exposure of glial cells to increasing concentrations of PGE(2) or other prostanoids did not increase TNF-alpha synthesis, while the presence of exogenous PGE(2) during treatment of glial cells with TMT actually suppressed TNF-alpha release. The activation of arachidonic acid metabolism produces reactive oxygen species (ROS). Scavenging of ROS by means of the antioxidant trolox prevented the TMT-induced release of TNF-alpha from glial cells, while indomethacin was found to suppress ROS formation induced by 1 microM TMT in glial cells. These results suggest that activation of arachidonic acid metabolism causes TNF-alpha release through the production of ROS rather than PGE(2). Indeed, PGE(2) may exert negative feedback on the release of TNF-alpha.

Animals↗

PubMed2002

Morphological alterations and elevations in tumor necrosis factor-alpha, interleukin (IL)-1alpha, and IL-6 in mixed glia cultures following exposure to trimethyltin: modulation by proinflammatory cytokine recombinant proteins and neutralizing antibodies.

Trimethyltin (TMT), is a hippocampal neurotoxicant characterized by neuronal degeneration, astrogliosis, and microglia reactivity with an associated elevation in proinflammatory cytokine mRNA levels. To examine the role of proinflammatory cytokines in the TMT-induced glia response, mixed cortical glia cultures were exposed to TMT and morphological and cytokine responses were examined. Morphological changes in the glia monolayer, enlarged, rounded cell bodies and retraction of the monolayer into distinct GFAP+ dense processes, displayed a dose (1, 5, and 10 microM TMT) and temporal response (6-48 h), accompanied by clustering of OX-42+ microglia. Tumor necrosis factor-alpha (TNF), interleukin (IL)-1alpha, and IL-6 mRNA levels were elevated by 3 and 6 h of TMT (10 microM) and proteins by 24 h. Recombinant proteins for IL-1alpha (100 pg/ml) and IL-6 (10 ng/ml) exacerbated the morphological response to TMT while those for TNFalpha (150 pg/ml) did not. Neutralizing antibodies (1:100) to IL-1alpha and IL-6 showed a slight decrease in the severity of the morphological response to TMT while, at 24 h, TNFalpha antibodies (1:100) and an antibody cocktail offered a significant level of protection. At 6 h, the neutralizing antibodies to TNFalpha or IL-1alpha did not elevate basal cytokine mRNA levels, however, IL-6 and the cocktail of antibodies significantly elevated IL-1alpha, IL-1beta, and IL-6 mRNA levels. The specific elevation in IL-1alpha and IL-6 mRNA levels induced by TMT remained evident only in cells coexposed to anti-TNFalpha. Similar responses in cytokine mRNA levels were seen in cocultures of hippocampal neurons and glia exposed to TMT. These data suggest a relationship between microglia activation, proinflammatory cytokine release, and glia morphological responses, the significance of which remains to be determined, as well as, the impact on neuronal degeneration.

Animals↗

PubMed1989

Presynaptic cholinergic action in the hippocampus.

The hippocampus is among the regions in the brain richest in M1 cholinergic receptors. Topical application of acetylcholine (ACh) onto hippocampal slices produces a characteristic complex response consisting of a depolarization, an increase in input resistance especially upon depolarization and a blockade of a slow afterhyperpolarization (AHP). The first two of these responses can be recorded also in non-cholinergic septal neurons in an area which contains about 8% of the M1 muscarinic receptors found in the hippocampus. The responses of hippocampal but not septal neurons to ACh involve an increase in the spontaneous synaptic activity and a decrease in evoked responses to afferent stimulation. The dissociated hippocampal culture was used to study these presynaptic effects. The neurons in culture possess muscarinic receptors which develop gradually over a period of several weeks after plating. ACh rarely depolarizes hippocampal neurons in culture. Instead, it causes an increase in spontaneous discharge of small postsynaptic currents (PSC's) and a marked decrease of large, evoked PSC's. In some cultured hippocampal cells ACh reduced ICa without affecting any of several outward K currents studied. It is suggested that ACh reduces evoked activity by reducing Ca currents at presynaptic terminals.

Acetylcholine↗

PubMed1995

Age-related alterations in cell division and cell cycle kinetics in control and trimethyltin-treated lymphocytes of human individuals.

Trimethyltin chloride induced age-related suppression of cell division and cell cycle kinetics in human peripheral blood lymphocytes cultured in RPMI 1640 culture medium supplemented with human AB serum, phytohemagglutinin and bromodeoxyuridine. A high frequency of M1 (first metaphase) cells was seen in cultures treated with a high dose (C1 = 1.0 microgram per culture) and in lymphocytes from donors in the age range 40-70 years. The delay in cell division and cell cycle kinetics may indicate a longer duration in DNA synthesis induced by trimethyltin chloride in aged lymphocytes.

Adenosine Triphosphate↗

PubMed1990

Regional variations in nerve cell responses to trimethyltin intoxication in Mongolian gerbils and rats; further evidence for involvement of the Golgi apparatus.

The different responses of neurons with distinctive variations in morphology and function, confirm earlier observations of the lack of uniformity in the reaction of nerve cells to trimethyltin. Thus, hippocampal pyramidal and cortical neurons in both rat and Mongolian gerbil (M. unguiculatus) show abundant lysosomal dense bodies and disorganisation of the protein-synthesising apparatus. Cerebellar Purkinje cells in gerbil, but not in rat, show striking increases in smooth membrane systems, while dense bodies are insignificant in both species; large motor-type neurons in brain stem and spinal cord in both species do not accumulate dense bodies, but their rough endoplasmic reticulum (RER) may undergo intense vacuolation with or without subsequent cell death; and by contrast, spinal ganglion cells of both species may form an excess of dense bodies and, in the gerbil, vacuolation of RER. In contrast with these varied responses to trimethyltin most neurons, large and small, in both species regularly undergo striking vacuolation of the Golgi apparatus in the earliest phase of the intoxication, a constant feature that probably reflects the site of the primary cytotoxic lesion; all other changes we consider are secondary to such damage to the Golgi apparatus, however this may come about. These observations are discussed in relation to earlier reports of the variable effects of trimethyltin and with the metabolic changes reported in trimethyltin intoxication that in general accord with these morphological conclusions.

Animals↗

PubMedDate not supplied

S-100 proteins in trimethyltin-induced neurodegeneration in the rat hippocampus. An immunochemical and immunocytochemical study.

After acute trimethyltin (TMT) intoxication (21 d after a single i.p. injection at a dose of 8 mg/kg) the histological, immunohistochemical, and immunochemical investigation of adult rat hippocampus showed a distinct pattern of neuronal loss, and an increase in both glial fibrillary acidic protein- (GFAP) immunoreactive cells and GFAP concentration, as expected. S-100-immunoreactive cells also increased markedly, whereas the concentration of S-100 increased even more than that of GFAP. The data show that S-100 is an index of glial reaction to damage after TMT intoxication and suggest the potential usefulness of exploring the possibility that it may play a role in induced neurodegenerative processes.

Animals↗

PubMed1994

Effects of trimethyltin (TMT) on choline acetyltransferase activity in the rat hippocampus. Influence of dose and time following exposure.

Trimethyltin (TMT) destroys specific subfields of the hippocampus in the rat. TMT also increases choline acetyltransferase (ChAT) activity in CA1 of Ammon's horn and the outer molecular layer of the dentate gyrus. This observation suggests that axonal sprouting occurs in the cholinergic septohippocampal system in response to TMT. However, neither does-response nor time course data are available for the effects of TMT on this enzyme. The effects of three dose levels of TMT on ChAT activity in CA1 and the dentate gyrus were determined in Experiment 1 and ChAT activity in these two areas was measured at six time points following exposure to TMT in Experiment 2. Only the highest dose of TMT (6 mg/kg) significantly increased ChAT activity. ChAT activity in the dentate gyrus increased significantly by 3 d after administration and continued to increase until 21 d after exposure. A significant increase was not observed in CA1 until 7 d after exposure to TMT. Asymptotic levels were still reached at d 21. These results indicate a steep dose-response curve for TMT-induced changes in ChAT activity in the hippocampal formation and that this marker of cholinergic activity is more sensitive to perturbation by TMT in the dentate gyrus than Ammon's horn.

Animals↗

PubMed1994

The effect of time following exposure to trimethyltin (TMT) on cholinergic muscarinic receptor binding in rat hippocampus.

Adult male Long-Evans rats were given 6 mg/kg trimethyltin (TMT). Rats were killed 1, 3, 7, 14, 21, 35, or 60 d later. An untreated control group was included. Brain sections were processed using film autoradiography to visualize in the hippocampus either total muscarinic receptor binding ([3H]quinuclidinyl benzilate; [3H]QNB), or M1 receptors ([3H]pirenzepine; [3H]PZ), or M2 receptors ([3H]oxotremorine-M; [3H]OXO-M). A reduction in [3H]QNB binding was found in CA1 and CA3c 7 d after TMT, but not in CA3a, b, or the dentate gyrus. [3H]PZ binding was decreased throughout Ammon's horn by 14 d after treatment. [3H]OXO-M binding decreased 1 d after exposure in CA1 and in all subfields of Ammon's horn by d 3. Neither [3H]PZ or [3H]OXO-M binding decreased in the dentate gyrus of TMT-treated rat at any time point. The temporal patterns of receptor loss may be explicable by reference to timing of fiber and cell body degeneration reported in previous studies and the regional differences may account for discrepancies between reports of either substantial decreases or no loss in hippocampal muscarinic receptors after TMT exposure.

Animals↗

PubMed2003

Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage.

The interactions of glia and neurons during injury and subsequent neurodegeneration are a subject of interest both in disease and chemical-induced brain injury. One such model is the prototypical hippocampal toxicant trimethyltin (TMT). An acute injection of TMT (2.0 mg/kg, i.p.) to postnatal day 21 CD-1 male mice produced neuronal necrosis and loss of dentate granule cells, astrocyte hypertrophy, and microglia activation in the hippocampus within 24 hrs. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-alpha, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-alpha mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h. Immunohistochemistry suggested a cellular localization of cyclin A to microglia in the region of neuronal necrosis in the dentate, cyclin B in glial cells in juxtaposition to neurons in the hilus of the hippocampus and cyclin D1 to non-glial cells in the dentate. mRNA levels for cyclin D1 were elevated approximately 1.5-fold by 72 h as determined by RNase protection assay. No changes were seen in mRNA levels for cyclins E, F, G1, G2, H or I nor cyclin dependent kinases. These elevations are not associated with proliferation of microglia as determined by BrdU incorporation and Ki-67 immunohistochemistry. Upregulation of cell cycle genes was associated with cellular processes other than proliferation and may contribute to the differentiation of microglia to a phagocytic phenotype. These data suggest an integrated role for cell cycle regulation of neural cells in the manifestation of hippocampal pathophysiology.

Animals↗

PubMed2004

Trimethyltin-induced neurogenesis in the murine hippocampus.

Neurogenesis continues to occur in the mature rodent brain with one of the most prominent sources for new neurons being the subgranular layer (SGL) of the dentate gyrus (DG) in the hippocampus. A number of factors can stimulate this process including synaptic activity and injury. To determine if this process would occur upon a direct injury to the dentate region, we exposed young, 21 day old male CD-1 mice to the hippocampal toxicant, trimethyltin (TMT). An acute i.p. injection of TMT (2 mg/kg) produced extensive damage and loss of dentate granule neurons within 72 h. This active period of degeneration was accompanied by an increase in the generation of progenitor cells within the SGL as identified by BrdU uptake and Ki-67 immunostaining. As additional markers for neurogenesis, both nestin and doublecortin showed increased staining patterns within the blades of the dentate. In these young weanling mice, the level of proliferation was sufficient to significantly repopulate the dentate region by 4 weeks post-TMT, suggesting a high level of regenerative potential. Our data indicate a significant level of neurogenesis occurring during the active process of degeneration and in an environment of microglia activation. The TMT-induced injury offers a model system for further examination of the process of neurogenesis, neural adaptation, and the influence of inflammatory factors and glia interactions.

Animals↗

PubMed2001

Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin.

Angiogenesis is a characteristic feature of many aggressive tumours and other disorders. Antibodies capable of binding to new blood vessels, but not to mature vessels, could be used as selective targeting agents for immunoscintigraphic and radioimmunotherapeutic applications. Here we show that scFv(L19), a recombinant human antibody fragment with sub-nanomolar affinity for the ED-B domain of fibronectin, a marker of angiogenesis, can be stably labelled with iodine-125 and astatine-211 with full retention of immunoreactivity, using a trimethyl-stannyl benzoate bifunctional derivative. Biodistribution studies in mice bearing two different types of tumour grafted subcutaneously, followed by ex vivo micro-autoradiographic analysis, revealed that scFv(L19) rapidly localises around tumour blood vessels, but not around normal vessels. Four hours after intravenous injection of the stably radioiodinated scFv(L19), tumour to blood ratios were 6:1 in mice bearing the F9 murine teratocarcinoma and 9:1 in mice bearing an FE8 rat sarcoma. As expected, all other organs (including kidney) contained significantly less radioactivity than the tumour. Since the ED-B domain of fibronectin has an identical sequence in mouse and man, scFv(L19) is a pan-species antibody and the results presented here suggest clinical utility of radiolabelled scFv(L19) for the scintigraphic detection of angiogenesis in vivo. Furthermore, it should now be possible to investigate scFv(L19) for the selective delivery of 211At to the tumour neovasculature, causing the selective death of tumour endothelial cells and tumour collapse.

Animals↗

PubMed2002

Neuronal degeneration and glial cell-responses following trimethyltin intoxication in the rat.

Trimethyltin (TMT) preferentially induces neuronal changes in the hippocampus and pyriform cortex. In the present study we investigated the time course of microglial and astroglial responses associated with neurodegeneration after the administration of TMT (i.p. 9 mg/kg or 12 mg/kg body weight) in the rat. At a dosage of 9 mg/kg TMT, neurodegeneration was clearly demonstrated in the CA1 and CA3 regions of the hippocampus as argyrophilic (dark) neurons by day 4 using the Gallyas-Braak (G-B) impregnation method that has been shown to be sensitive and specific for neurodegeneration. Early microglial response was immunohistochemically shown with anti-microglial response factor-1 (MRF-1) antibody in the CA3 by day 1, preceding neurodegeneration morphologically detected by the G-B method. Activation of astrocytes was revealed by immunohistochemical staining for glial fibrillary acidic protein (GFAP) by day 2. In parallel with the maximal neurodegeneration, large numbers of hypertrophied microglia and astrocytes were observed in the CA1 and CA3 by day 7. Numbers of degenerative neurons appeared to be closely associated with adjacent microglia by the double staining of G-B impregnation and MRF-1 immunohistochemistry. The number of reactive microglia considerably decreased to the resting state by day 14, while hypertrophied astrocytes were still prominent in the CA3 up to day 21. With the high dose of TMT, granule cells in the dentate gyrus and CA1 and CA3 pyramidal cells were significantly impregnated. After TMT treatment, accompaning neurodegeneration we observed early response of microglia and prolonged activation of astrocytes, suggesting an individual role of glial cells in maintenance and repair of damaged neurons following brain injury.

Animals↗

PubMed1989

Electron spin resonance measurements of the effect of ionophores on the transmembrane pH gradient of an acidophilic bacterium.

The delta pH in ionophore-treated cells of an acidophile has been determined by electron spin resonance spectroscopy. The values obtained were comparable to those obtained using the more conventional techniques involving radiolabeled probes. No binding of the spin-labeled probe was observed as determined by two independent control experiments and by the characteristics of the probe signal. These results led us to conclude that the delta pH measured in protonophore/ionophore-treated cells is a result of a Donnan potential, which may be a physical property of all intact bacterial cells at low pH values.

Bacillus↗

PubMed1992

Interactions of trimethyl tin (TMT) with rat primary astrocyte cultures: altered uptake and efflux of rubidium, L-glutamate and D-aspartate.

Studies were undertaken to assess the effects of trimethyl tin (TMT) on metabolic functions in primary neonatal rat cultured astrocytes. Concentrations as low as 10(-5) M TMT significantly inhibited the initial rate (1 min) of uptake of 86RbCl, used as a tracer for K+. TMT also markedly inhibited the initial rate (1 min) of Na(+)-dependent uptake of L-[3H]glutamate and D-[3H]aspartate, and stimulated the release of intracellular 86Rb+, -[3H]glutamate and D-[3H]aspartate in a dose-dependent fashion. These observations support the hypothesis that the astrocyte plasma membrane is potentially an important target for TMT's toxic effect and specifically that small concentrations of this organometal can inhibit the ability of astrocytes to maintain a transmembrane K+ gradient. This would be expected to compromise the ability of astrocytes to control extracellular K+ either by spatial buffering or active uptake, and exacerbate on-going swelling. Increased levels of glutamate and aspartate in the extracellular fluid upon release from astrocytes may play an important role in TMT neurotoxicity.

Animals↗

PubMed1996

Nitric oxide synthase-containing neurons in the hippocampus are preserved in trimethyltin intoxication.

We studied the effects of trimethyltin (TMT) (9 mg/kg, p.o.) on the nitric oxide synthase (NOS)-containing neurons in the rat hippocampus by NADPH-diaphorase histochemistry and a biochemical assay of NOS activity. TMT exposure caused the typical behavioral changes and a loss of the CA3/4 pyramidal cells, which were NADPH diaphorase-negative. The scattered interneurons and the CA1 pyramidal cells, which were NADPH diaphorase-positive, were spared. Hippocampal NOS activity showed no reduction in the TMT-treated rats compared with the controls. These results provide evidence of the preservation of the NOS-containing neurons in TMT intoxication.

Animals↗

PubMed1990

A comparison of the psychopharmacological profiles of phencyclidine, ketamine and (+) SKF 10,047 in the trimethyltin rat model.

The potential neuroprotective effects of phencyclidine, ketamine and (+) SKF 10,047 were investigated in the trimethyltin (TMT)-treated rat. Of the three drugs used in this study, only phencyclidine (5 mg/kg i.p.) reversed the behavioral hyperactivity and deficits in spatial localization of TMT-treated rats. Neurochemically, phencyclidine and (+) SKF 10,047 were without effect on the neurotransmitters (e.g. noradrenaline, dopamine, serotonin and 5-hydroxindole 3-acetic acid), examined in the amygdaloid cortex and hippocampal regions, while ketamine increased the steady state concentrations of 5-HIAA in the amygdaloid cortex. These results suggest the involvement of the phencyclidine receptor in reversal of the behavioural impairments produced by TMT in rats. The significance of these results with respect to phencyclidine and sigma receptors is discussed. The lack of effect of (+) SKF 10,047 in this model may reflect behavioural differences between phencyclidine and sigma ligands. It may be concluded that the TMT model can be exploited for studying the mechanism of action of molecules liable to have an effect at the phencyclidine receptor site, as opposed to the sigma receptor.

Animals↗

PubMed1994

Effects of trimethyltin on acquisition and reversal of a light-dark discrimination by rats.

The behavioral deficits produced by trimethyltin (TMT) are usually attributed to the hippocampal damage caused by this toxicant. The purpose of this experiment was to determine the effects of TMT administration on acquisition and reversal of a discrete trial light-dark discrimination. Acquisition of this task is impaired by hippocampal lesions but the effects of TMT on it are not known. Forty-five days after some of the rats were given one of three doses of TMT, adult, male Long-Evans rats were given 100 trials per day for 20 days to acquire a discrete trial lever press discrimination with lit cue lights located above the correct lever. At the end of this time the contingencies were reversed and the rats were given 30 more days of training. No significant group differences occurred during the first 20 days. A significant group effect was found for the 30 days of reversal training. The rats given the highest dose of TMT (6 mg/kg) obtained significantly more reinforcements during reversal training than the other groups. Because surgical hippocampal lesions generally impair both acquisition and reversal of visual discriminations, these data were unexpected and suggest that other factors than hippocampal damage enter into the behavioral effects of TMT.

Animals↗