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PubMed1998

Cellular localization and temporal elevation of tumor necrosis factor-alpha, interleukin-1 alpha, and transforming growth factor-beta 1 mRNA in hippocampal injury response induced by trimethyltin.

In certain pathologic states, cytokine production may become spatially and temporally dysregulated, leading to their inappropriate production and potentially detrimental consequences. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-beta) mediate a range of host responses affecting multiple cell types. To study the role of cytokines in the early stages of brain injury, we examined alterations in the 17-day-old mouse hippocampus during trimethyltin-induced neurodegeneration characterized by neuronal necrosis, microglia activation in the dentate, and astrocyte reactivity throughout the hippocampus. By 24 h after dosing, elevations in mRNA levels for TNF-alpha, IL-1alpha, IL-1beta, and IL-6 mRNA were seen. TGF-beta1 mRNA was elevated at 72 h. In situ hybridization showed that TNF-alpha and IL-1alpha were localized to the microglia, whereas TGF-beta1 was expressed predominantly in hippocampal pyramidal cells. Intercellular adhesion molecule-1, EB-22, Mac-1, and glial fibrillary acidic protein mRNA levels were elevated within the first 3 days of exposure in the absence of increased inducible nitric oxide synthetase and interferon-gamma mRNA. These data suggest that pro-inflammatory cytokines contribute to the progression and pattern of neuronal degeneration in the hippocampus.

Animals↗
PubMed2000

Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity.

The peripheral benzodiazepine receptor (PBR) is currently used as a marker of inflammation and gliosis following brain injury. Previous reports suggest that elevated PBR levels in injured brain tissue are specific to activated microglia and infiltrating macrophages. We have produced hippocampal lesions using the neurotoxicant trimethyltin (TMT) to examine the cellular and subcellular nature of the PBR response. Degenerating, argyrophilic pyramidal neurons were observed in the hippocampus at 2 and 14 days after TMT exposure. Reactive microglia were also evident at both times with a maximal response observed at 14 days, subsiding by 6 weeks. Astrocytosis was observed at 14 days and 6 weeks, but not 2 days, after TMT administration, suggesting that the onset of the astroglia response is delayed, but more persistent, compared with microgliosis. Morphological evidence from [3H]PK11195 microautoradiography and PBR immunohistochemistry indicates that both astrocytes and microglia are capable of expressing high levels of PBR after injury. This was confirmed by double labeling of either Griffonia simplicifolia isolectin B4, a microglial-specific marker, or glial fibrillary acidic protein, an astrocyte-specific protein with PBR fluorescence immunohistochemistry. These results demonstrate that PBR expression is increased after brain injury in both activated microglia and astrocytes. Our findings also provide the first evidence for in situ nuclear localization of PBR in glial cells.

Animals↗
PubMed2003

In vivo neuroprotective role of NMDA receptors against kainate-induced excitotoxicity in murine hippocampal pyramidal neurons.

Activation of NMDA receptors has been shown to induce either neuronal cell death or neuroprotection against excitotoxicity in cultured cerebellar granule neurons in vitro. We have investigated the effects of pretreatment with NMDA on kainate-induced neuronal cell death in mouse hippocampus in vivo. The systemic administration of kainate (30 mg/kg), but not NMDA (100 mg/kg), induced severe damage in pyramidal neurons of the hippocampal CA1 and CA3 subfields 3-7 days later, without affecting granule neurons in the dentate gyrus. An immunohistochemical study using an anti-single-stranded DNA antibody and TdT-mediated dUTP nick end labeling analysis both revealed that kainate, but not NMDA, induced DNA fragmentation in the CA1 and CA3 pyramidal neurons 1-3 days after administration. Kainate-induced neuronal loss was completely prevented by the systemic administration of NMDA (100 mg/kg) 1 h to 1 day previously. No pyramidal neuron was seen with fragmented DNA in the hippocampus of animals injected with kainate 1 day after NMDA treatment. The neuroprotection mediated by NMDA was prevented by the non-competitive NMDA receptor antagonist MK-801. Taken together these results indicate that in vivo activation of NMDA receptors is capable of protecting against kainate-induced neuronal damage through blockade of DNA fragmentation in murine hippocampus.

Animals↗
PubMed1996

Rat strain- and gender-related differences in neurobehavioral screening: acute trimethyltin neurotoxicity.

Trimethyltin (TMT) produces unique pathological and behavioral changes after a single dose. In this study, TMT was used to examine the ability of a neurobehavioral screening battery (functional observational battery and motor activity) to characterize these behavioral changes in rats. The behavioral profile of TMT was obtained using these tests in male Long-Evans (LE) and Fischer 344 (F344) rats, to assess the influence of rat strain, and in LE males and females to evaluate gender-related differences. All rats were tested before dosing and again at 1, 7, 21, and 42 d after a single dose of either 0, 4, 6, or 8 mg/kg TMT-hydroxide (intravenously). In general, the characteristic syndrome of tremor, increased reactivity, and hyperactivity was observed; however, the magnitude and time course of these effects were much greater in F344 rats. Significant strain- but not gender-related differences were obtained when comparing TMT effects on different domains of neurological function. Comparisons of predosing data between male LE and F344 rats, as well as between male and female LE rats, revealed significant differences in baseline values for about half of the measures of the test battery. These preexisting differences, however, could not account for the observed dissimilarities in treatment effects. Quantitative and qualitative differences were evident to a greater extent when comparing LEs and F344s than between males and females. Therefore, conclusions based on these types of neurobehavioral screening data would be influenced considerably more by the differences between rat strains.

Analysis of Variance↗
PubMed1999

Biokinetics of the monoclonal antibodies MOv 18, OV 185 and OV 197 labelled with 125I according to the m-MeATE method or the Iodogen method in nude mice with ovarian cancer xenografts.

The biodistribution of the radiolabelled monoclonal antibodies MOv18, OV185 and OV197 in nude mice with subcutaneous tumours of the human ovarian cancer cell line OVCAR3 was investigated. The early uptake of MOv18 (1-24 h) and the uptake in relation to tumour size were also studied. The antibodies were labelled with 125I according to the Iodogen method or the m-MeATE method, the latter also being suitable for labelling with 211Astatine. The tumour/blood ratio and the localization index for Mov 18 72 h after antibody injection were 2.21 +/- 0.25 and 4.62 +/- 1.27, respectively. This is significantly higher than for the other two specific antibodies. The early tumour uptake of MOv18 was low with a tumour/blood ratio of 0.23 +/- 0.04 after 6 h, and the uptake was higher in small tumours. The two labelling methods were found to be equivalent. We conclude that MOv18 labelled according the m-MeATE method should be suitable for further therapeutic studies with 211Astatine in nude mice.

Animals↗
PubMed1991

Comparison of rats of the Fischer 344 and Long-Evans strains in their autonomic thermoregulatory response to trimethyltin administration.

The purpose of this study was to assess the effect of genetic strain on the acute and long-term thermoregulatory response to the neurotoxicant trimethyltin (TMT) in rats of the Long-Evans (LE) and Fischer 344 (FCH) strains. In one study basic thermoregulatory responses including colonic temperature (Tc), metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), and thermal conductance (Cd) were measured in both rat strains at ambient temperatures (Ta) of 10, 28, and 37 degrees C. It was found that the LE rat has a significantly higher Tc when it is measured in their home cage. Because of its smaller body mass the FCH rat has a higher MR at all Ta values. The FCH rat also has a greater rate of EWL during exposure to a Ta of 37 degrees C. Following iv administration of 8.0 mg/kg TMT both rat strains become significantly hypothermic; however, the effect differed significantly between the strains. At 26-34 d after TMT exposure thermoregulatory responses at Ta values of 10-37 degrees C were generally similar to that of the saline controls. Overall, the LE and FCH strains of rat exhibit some distinct thermoregulatory differences in response to changes in Ta.

Animals↗
PubMed2001

Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells.

In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 microM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H(2)O(2) are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative species generation, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 microM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.

Alkaloids↗
PubMed1992

Ubiquitin, PGP 9.5 and dense body formation in trimethyltin intoxication: differential neuronal responses to chemically induced cell damage.

Ubiquitin in normal cells may be important in degrading or transferring short-lived or aberrant proteins to lysosomal dense bodies. To examine its role in degrading proteins produced by a chemical insult, changes in the distribution of ubiquitin and the carboxy-terminal hydrolase, PGP 9.5, have been studied in rat hippocampal neurons and cerebellar Purkinje cells in trimethyltin intoxication. Here tubulovesicular dense bodies (TVBs) form from 12h onwards associated with vacuolation of the Golgi apparatus. Striking accumulations of lysosomal dense bodies follow in hippocampal pyramidal cells but not in cerebellar Purkinje cells; many of the hippocampal neurons later die, while the Purkinje cells generally survive. Ubiquitin immunoreactivity was diffusely increased in hippocampal pyramidal and Purkinje cells 6 h after dosing. By 12 h both diffuse and granular ubiquitin immunoreactivity was present that intensified over 24 and 48 h. Both by light and electron microscopy TVBs showed ubiquitin immunoreactivity, but dense bodies in hippocampal perikarya did not stain with an anti-ubiquitin antibody. PGP 9.5 immunoreactivity was not altered in hippocampal cells at any time, while Purkinje and Golgi cell dendrites and perikarya showed intensified labelling at 3 h that reached a peak of 12 h. At 48 h Western blot analysis of hippocampal homogenates showed significant increases in high molecular weight (HMW) ubiquitin conjugates, while cerebellar homogenates showed an increase in ubiquitin-histone conjugates. Northern blot analyses showed no change in ubiquitin or PGP9.5 gene expression in hippocampus or cerebellum. These findings suggest that the material in the TVBs in hippocampal cells is not being degraded by the ubiquitin system but passes ubiquitinated into the lysosomal system, while material in Purkinje cell TVBs is degraded by the ubiquitin system, suggesting it may have a different composition in each type of neuron.

Animals↗
PubMed2006

Expression of microsomal epoxide hydrolase is elevated in Alzheimer's hippocampus and induced by exogenous beta-amyloid and trimethyl-tin.

The brain is a potential target for drugs and environmental toxins. Microsomal epoxide hydrolase (mEH) is one of several critical biotransformation enzymes in xenobiotic metabolism and detoxification. In the present study, we report that the expression of mEH is significantly elevated in the hippocampus and associated cortex, but not in the cerebellum, in Alzheimer's disease (AD) patients. A large proportion of the mEH-positive cells are located around beta-amyloid plaques. The mEH-positive-staining cells are astrocytes and pyramidal neurons. Western blotting analysis confirmed increased expression of mEH in AD hippocampal tissues. In primary hippocampal glial culture, beta-amyloid aggregation stimulated mEH expression in the astrocytes, which displayed a patchy distribution. An environmental neurotoxic agent, trimethyl-tin, also activated mEH expression in rat hippocampus and entorhinal cortex. The present study demonstrates a significant increase in mEH expression in the AD hippocampus, a region showing abundant neuropathology in AD. The expression of mEH could also be elevated by exposure to exogenous beta-amyloid in vitro and environmental toxins in vivo. Our studies suggest that mEH may play a role in pathogenesis of neurodegeneration in response to environmental stress.

Aged↗
PubMed1991

Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury.

Short (5 days)- to long-term (4 months) corticosterone (CORT) administration by injection, pellet implantation, or in the drinking water decreased glial fibrillary acidic protein (GFAP) by 20-40% in hippocampus and cortex of intact rats. In contrast to CORT, adrenalectomy (ADX) caused elevations (50-125%) in hippocampus and cortex GFAP within 12 days of surgery that persisted for at least 4 months. CORT replacement of ADX rats decreased GFAP amount in hippocampus and cortex. The effects of long-term CORT and ADX on GFAP in hippocampus and cortex were also seen in striatum, midbrain, and cerebellum, findings suggestive of brain-wide adrenal steroid regulation of this astrocyte protein. The changes in GFAP amount due to CORT and ADX were paralleled by changes in GFAP mRNA, indicating a possible transcriptional or at least genomic effect of adrenal steroids. Glucocorticoid regulation of GFAP was relatively specific; it could not be generalized to other astrocyte proteins or other major structural proteins of neurons. The negative regulation of GFAP and GFAP mRNA by adrenal steroids suggested that increases in GFAP that result from brain injury may be attenuated by glucocorticoids. However, chronic CORT treatment of intact rats did not reverse or reduce the large increases in GFAP caused by trauma- or toxicant-induced brain damage. Thus, glucocorticoids and injury appear to regulate the expression of GFAP through different mechanisms. In contrast to the lack of effects of CORT on brain damage-induced increases in GFAP, CORT treatment begun in 2-week ADX rats, after an increase in GFAP had time to occur, did reverse the ADX-induced increase in GFAP. These results suggest that the increase in GFAP resulting from ADX is not mediated through an injury-linked mechanism.

Actins↗
PubMed2005

Molecular profiles of mRNA levels in laser capture microdissected murine hippocampal regions differentially responsive to TMT-induced cell death.

Using a chemical-induced model of dentate granule (DG) cell death, cDNA microarray analysis was used to identify gene profiles from the laser-captured microdissected (LCM) hippocampal DG cell region versus the CA pyramidal cell layer (CA) from 21-day-old male CD1 mice injected with trimethyltin hydroxide (TMT; 3.0 mg/kg, i.p.). At 6 h post-TMT, lectin + microglia displaying a reactive morphology were in contact with active caspase 3+ neurons. By 18 h, amoeboid microglia and signs of phagocytosis, and a mild astrocytic response were present in the DG. There was no evidence of IgG extravasation in the hippocampus, or cell death and glial reactivity in the CA. Atlas 1.2K Clontech array detected 115 genes changed in the hippocampus with TMT and included genes associated with immediate-early responses, calcium homeostasis, cellular signaling, cell cycle, immunomodulation and DNA repair. Early responses localized to LCM DG samples consisted of elevations in inflammatory factors such as tumor necrosis factor-alpha and receptors, as well as MIP1alpha, CD14, CD18, and a decrease in factors associated with calcium buffering. By 18 h, in the DG, changes occurred in transcripts associated with apoptosis, cell adhesion, DNA repair, cell proliferation and growth. In the CA, a differential level of elevation was seen in CD86 antigen, zinc finger protein 38 and DNA damage inducible transcript 3. A significant number of genes was decreased at these early time points in both hippocampal regions.

Animals↗
PubMed1996

The sigma ligand JO 1784 prevents trimethyltin-induced behavioural and sigma-receptor dysfunction in the rat.

Recently much research interest has focused on the possible therapeutic uses of sigma-receptor ligands in psychiatric and neurodegenerative disorders. In the present study, the potential neuroprotective effects of chronic (52 days) administration of (+) cinnamyl-l-phenyl-l-N-methyl-N-cyclo propylene (JO 1784) (1 and 3 mg/kg subcutaneously), a potent and selective sigma receptor ligand, were assessed in the trimethyltin (8 mg/kg intraperitoneally) model of memory dysfunction. JO 1784 (3 mg/kg subcutaneously) prevented the trimethyltin-induced deficits in locomotor activity, passive avoidance and radial maze performance, while the lower dose of JO 1784 had little or no effect. Trimethyltin was also shown to produce a marked reduction in the binding of [3H] (+)-pentazocine to sigma-receptor sites in limbic brain structures, as detected by quantitative autoradiography, which was particularly evident in the hippocampal pyramidal cells. JO 1784 (3 mg/kg subcutaneously) successfully attenuated this loss of [3H] (+)-pentazocine binding sites in the hippocampus (CA1, CA3 and CA4 regions) and in the substantia innominata. This neuroprotective effect of JO 1784 in the trimethyltin model would seem to be related to the modulatory effects of this sigma ligand on trimethyltin-induced glutamate neurotoxicity.

Animals↗
PubMed1993

Developmental differences in neural damage following trimethyl-tin as demonstrated with GFAP immunohistochemistry.

Long-Evans rat pups received intraperitoneal (i.p.) injections of trimethyl-tin (TMT) 6 mg/kg hydroxide or saline on postnatal day (PND) 10 or PND 18 and were sacrificed for immunohistochemical staining for glial fibrillary acidic protein (GFAP) on PND 12, 18, 20, or 25. After dosing with TMT on PND 10 there was a transient increase in GFAP immunoreactivity (IR) in the amygdala, piriform, and entorhinal cortex 2 days post-dosing (PND 12) and a persistent increase in GFAP IR in the hippocampus and cingulate cortex up to two weeks post-dosing. Following dosing with TMT on PND 18 there was a delayed (PND 25) increase in GFAP IR in the amygdala, hippocampus, cingulate, piriform, and entorhinal cortex. In addition, increases in GFAP IR were observed in the neocortex 7 days post-dosing, which was not observed following earlier postnatal dosing. The regions in which gliosis and loss of Nissl-staining were consistent for the different time points of TMT treatment were the amygdala, hippocampus, cingulate, piriform, and entorhinal cortex. The present findings indicate the GFAP immunohistochemistry can be used to reveal regional effects of developmental neurotoxicant exposure during early stages of development.

Animals↗
PubMed2005

Protein kinase C epsilon regulates tumor necrosis factor-alpha-induced stannin gene expression.

Stannin (Snn) is a highly conserved vertebrate protein that has been closely linked to trimethyltin (TMT) toxicity. We have previously demonstrated that Snn is required for TMT-induced cell death. Others have shown that TMT exposure results in tumor necrosis factor-alpha (TNFalpha) production and that TNFalpha treatment induces Snn gene expression in human umbilical vein endothelial cells (HUVECs). In this study, we investigated a signaling mechanism by which Snn gene expression is regulated by TMT and demonstrated that TNFalpha stimulates Snn gene expression in a protein kinase C epsilon-dependent manner in HUVECs in response to TMT exposure. Supporting this, we show that TMT-induced toxicity is significantly blocked by pretreatment with an anti-TNFalpha antibody in HUVECs. Using a quantitative real-time polymerase chain reaction assay, we also show that the level of Snn gene expression is significantly increased in HUVECs in response to either TMT or TNFalpha treatment. This TNFalpha-induced Snn gene expression is blocked when HUVECs were pretreated with bisindolylmaleimide I, an inhibitor of protein kinase C (PKC). In contrast, when HUVECs were treated with phorbol 12-myristate 13-acetate, a PKC activator, we observed a significant increase in Snn gene expression. Using isotype-specific siRNA against PKC, we further show that knockdown of PKC epsilon, but not PKC delta or PKC zeta, significantly blocked TNFalpha-induced Snn gene expression. Together, these results indicate that TNFalpha-induced, PKC epsilon-dependent Snn expression may be a critical factor in TMT-induced cytotoxicity.

Cell Death↗
PubMed2005

Detection of electrophysiological indicators of neurotoxicity in human and rat brain slices by a three-dimensional microelectrode array.

Electrophysiological techniques for the assessment of in vitro neurotoxicology have several advantages over other currently-used methods (for example, morphological techniques), including the ability to detect damage at a very early stage. Novel recording techniques based on microelectrode arrays are available, and could improve recording power. In this study, we investigated how a three-dimensional microelectrode array detects the electrophysiological endpoints of neurotoxicity. We conclude that electrophysiology sensitively reveals neurotoxic actions, and that three-dimensional microelectrode arrays could be proposed for use in neurotoxicology as recording tools that allow easy and sensitive multisite recording, from both rodent and human brain tissue.

Animals↗