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PubMedDate not supplied

Drug effects on response-duration differentiation. IV: Effects of trimethyltin.

Trimethyltin (TMT) is a toxicological agent that produces damage in a number of limbic structures, resulting in concomitant disruptions of behavior. The purpose of the present study was to determine the utility of response-duration differentiation (RDD) responding as a behavioral baseline for studying the behavioral consequences of TMT administration. Under the RDD schedule, responses of a restricted duration (1-1.3 s) were reinforced, and disruption of this performance may represent effects upon fine motor control, timing behavior, or both. Two doses of TMT (4 mg/kg) were administered 1 week apart, and behavior under the schedule was studied daily for 6 weeks thereafter in a group of four rats. Additionally, the effects of diazepam (0.1-3mg/kg) administered prior to and following TMT administration were compared. TMT produced disruptions in accuracy of responding and increases in rates of responding in the weeks following its administration. Behavior had generally recovered by 6 weeks after the first TMT administration. Diazepam flattened the relative frequency distributions of response durations at lower doses in the TMT-treated rat. These data show that RDD responding is sensitive to the effects of TMT, and TMT treatment can result in alterations in the effects of diazepam.

Animals↗

PubMedDate not supplied

Acute trimethyltin exposure produces nonspecific effects on learning in rats working under a multiple repeated acquisition and performance schedule.

Previous research has explored the adverse effects of trimethyltin (TMT) on learning and memory in laboratory animals. Virtually all studies of TMT effects on learning have not, however, included appropriate controls to establish a selective effect on learning. This experiment investigated the effects of TMT on the repeated acquisition (learning) and performance of response sequences. Adult male Long-Evans rats, maintained at 300 g b.wt., were trained with food reinforcement under a multiple repeated acquisition (RA) and performance (P) schedule. The RA component required rats to learn a different three-member response sequence during each session (Center Right Left, RLC, RCL, LCR, or LRC); the correct response sequence remained constant in the P component (CLR). RA and P components alternated twice during a session. Rats were given 0, 4, or 8 mg/kg TMT IV after 30 sessions of stable baseline performance, and an additional 40 sessions were conducted following TMT. Prior to TMT, all groups maintained comparable accuracy levels in both RA and P components. Following TMT, significant decreases in both accuracy and response rate were obtained in the 8 mg/kg group. Thereafter, response rate and accuracy both recovered to near baseline levels, although large individual differences were observed. No selective effects of TMT were obtained on RA when compared to P. These data suggest that TMT-induced impairments on learning may be due to a generalized performance decrement rather than a specific effect on learning.

Animals↗

PubMed1994

Solid Me3Sn(O2CH): molecular and spin dynamics as viewed by 1H, 13C and 119Sn nuclear magnetic resonance spectroscopy.

Because of favourable dynamic properties in the solid state, crystalline trimethyltin formate, Me3Sn(O2CH), 1, offers quite unique possibilities to probe questions related to molecular dynamics (2 pi/3 Me3Sn reorientation) and to structural aspects (rigidity of the polymeric backbone, effectively isolated 1H-13C spin pair in the bidentate chain-building formate anion) by 1H, 13C and 119Sn high-resolution solid-state nuclear magnetic resonance (NMR) methods. The combined use of various one- (1D) and two-dimensional (2D) variable-temperature NMR experiments, including consideration of the short-time-cross-polarization (CP) behaviour of the 1H-13C spin pair in 13C-labelled Me3Sn(O2*CH), 1*, yields a fairly comprehensive description of the solid-state structure of 1, also in the absence of the single-crystal X-ray structure determination of 1. Taking advantage of the anisotropic polarization transfer within the formate 1H-13C spin pair allows to relate the orientation of the 1H-13C dipolar interaction, i.e. the C-H bond direction to the principal axes system of the 13C shielding tensor of the formate 13C from static 13C powder patterns of 1*.

Anisotropy↗

PubMed2005

A facile method for post-conjugation prosthetic radioiodination of "mini-peptides".

Prosthetic radioiodination methods were developed to facilitate the labeling of proteins devoid of tyrosine(s) or when these moieties are crucial for biological activity. This method involves the use of the so-called Bolton-Hunter-type reagents. However, the in vivo instability of the label prompted the search for more stable groups. Although these second generation reagents have worked well with proteins and peptides, the current reaction scheme takes a long time to perform. A simplified method may be more appropriate especially from radiation safety point of view. More importantly, for short-lived halogens, advantage may be gained utilizing a shorter reaction time. Recently we reported on the radioiodination of interleukin-8 (IL-8) using the pyridine carboxylate-derived activated ester. We have successfully conjugated this prosthetic group to tri- and tetrapeptides harboring the somatostatin (SST) receptor recognition units and characterized by HPLC and MS. The radioiodination was accomplished using the Iodogen method in a reasonable yield (mean=60%). The total synthesis time was approximately 60 min, which was 3-4 times shorter than the classical two-step method. Preliminary biodistribution of the radiolabeled peptide showed uptake in some of the organs known to express SST receptors. Injection of a low specific activity tracer significantly decreased the retention of radioactivity in these organs.

Animals↗

PubMed2005

Oxiracetam pre- but not post-treatment prevented social recognition deficits produced with trimethyltin in rats.

The social recognition paradigm was used to investigate the effect of trimethyltin (TMT) in adult male rats. Consequently, the effect of chronic oxiracetam (OXI) treatment in TMT impaired animals was evaluated. In all experiments, a behavioural testing was performed 3 weeks after TMT administration. Experiment 1: A single TMT oral dose, 5 and 7.5 but not 2.5mg/kg, impaired the natural ability of the adults to recognize a juvenile conspecific that they encountered 30 min before. The dose of 5mg/kg TMT was chosen to be used in subsequent experiments. Experiment 2: Chronic OXI pre-+post-treatment, daily 3 or 30 mg/kg sc for 7 days before and 7 days after the insult, protected the adults against recognition deficit produced by TMT. Experiment 3: OXI pre- but not post-treatment (always 3 and 30 mg/kg) had beneficial effects on the social recognition. The findings suggest that social recognition ability of adult male rats pre-treated sufficiently long with OXI is resistant to the neurotoxicity effect of TMT.

Analysis of Variance↗

PubMed2006

TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin.

We examined the expression and cellular localization of tumor necrosis factor alpha (TNFalpha) and its type 1 receptor (TNFR1) in mixed neuronal-glial cultures of rat hippocampal dentate gyrus exposed to glutamate (GLU) or trimethyltin (TMT). Our previous studies demonstrated that both pathogenic factors evoked neuronal apoptosis, however, TMT was more potent and caused cell death in almost 90% of neurons. Observed neurodegeneration was accompanied by morphological changes of microglia. In the current study, using RT-PCR and Western blotting analysis, we found that GLU and TMT induced increase in TNFalpha mRNA and protein levels. The induction of transcription was stronger following GLU treatment, however the protein production was much more intensive after TMT exposure. Double fluorescent labeling for TNFalpha, TNFR1 and cellular markers revealed cytokine expression in microglia and some neurons. On the other hand, majority of neuronal cells displayed TNFR1 immunoreactivity, in control and in treated cultures. Moreover, TMT led to a strong increase in TNFR1 expression in astrocytes, which displayed remarkable, granular staining for the cytokine receptor. Western blotting for TNFR1 revealed enhanced protein expression only in cultures treated with TMT. This is the first report demonstrating the changes of expression of TNFalpha and TNFR1 in hippocampal dentate gyrus cultures treated with GLU or TMT. Our results indicate that TNFalpha may be involved in the mechanism of neurotoxic effects evoked by both pathogenic factors and suggest that astrocytes via TNFR1 may enhance TMT-induced injury.

Animals↗

PubMed2005

Enhanced neurogenesis during trimethyltin-induced neurodegeneration in the hippocampus of the adult rat.

The occurrence of neurogenesis in the hippocampus of the adult rat during trimethyltin (TMT)-induced neurodegeneration was investigated using bromodeoxyuridine (BrdU). Fifteen days after TMT intoxication, BrdU-labeled cells were significantly more numerous in the hippocampus of treated animals, gradually decreasing towards the control value 21 days after intoxication in the dentate gyrus (DG), while in the CA3/hilus region BrdU-labeled cells were still more numerous in TMT-treated rats. In order to investigate the fate of newly-generated cells double labeling experiments using neuronal or glial markers were performed. Colocalization of the neuronal marker NeuN was detected in many BrdU-positive cells in the DG, while in the CA3/hilus region no colocalization of NeuN and BrdU could be observed. No colocalization of BrdU and the astroglial marker GFAP or the microglial marker OX-42 was detected either in the DG and or in the CA3/hilus region. The results indicate an enhancement of endogenous neurogenesis in the hippocampus during TMT-induced neurodegeneration, with the development of a subpopulation of regenerated cells into neurons in the DG, while in the CA3/hilus region the population of newly-generated cells should be regarded as undifferentiated.

Animals↗

PubMed2004

Trimethyltin-induced differential expression of PAR subtypes in reactive astrocytes of the rat hippocampus.

Thrombin, its main inhibitor (protease nexin-1) and its related receptors (protease-activated receptors, PAR-1,-2, -3, -4) were studied in rat hippocampus following administration of trimethyltin (TMT), a neurotoxin inducing neuronal degeneration and reactive gliosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry revealed that while expression of prothrombin and protease nexin-1 did not change significantly in TMT-treated hippocampi, PARs (in particular PAR-1 and to a lesser extent PAR-2 and PAR-3) were upregulated in reactive astrocytes, suggesting their involvement in neurodegeneration and in the consequent response of the nervous tissue.

Animals↗

PubMed2005

The protein stannin binds 14-3-3zeta and modulates mitogen-activated protein kinase signaling.

The molecular mechanisms underlying the selective toxicity of trimethyltin (TMT) remain unclear. Stannin (Snn), a protein preferentially expressed in TMT-sensitive cells, provides a direct link to the molecular basis for TMT toxicity. Recent evidence demonstrated that Snn peptides bind and de-alkylate TMT to dimethyltin (DMT); Snn may mediate both TMT and DMT toxicity. In this study, we demonstrate that Snn co-immunoprecipitates with a scaffolding protein 14-3-3, specifically with 14-3-3zeta isotype. Consistent with this, a detailed amino acid sequence analysis shows that Snn contains a putative 14-3-3 protein-binding site located within its hydrophilic loop. In addition, we present the evidence that Snn overexpression results in reduced extracellular regulated kinase activation and increased p38 activation. In contrast, the activity of c-Jun N-terminal kinase did not change following Snn overexpression. This is the first evidence that demonstrates a direct interaction between Snn and MAPK signaling molecules. Together, these findings indicate a role of Snn in modulation of MAPK signaling pathways through its interactions with 14-3-3zeta.

14-3-3 Proteins↗

PubMed2004

Expression of astrocytic nestin in the rat hippocampus during trimethyltin-induced neurodegeneration.

In this study we used an immunocytochemical approach to study nestin expression in the rat hippocampus during trimethyltin-induced neurodegeneration at different time points (5, 10, 15, 21 and 50 days) after intoxication. Nestin is transiently expressed by a subpopulation of astroglial cells strictly associated with pyramidal neurons in those hippocampal areas severely affected by degeneration. This observation shows that cerebral tissue re-expresses this developmental protein during neurodegenerative diseases in early stages of astroglial activation.

Animals↗

PubMed2006

Corticosterone regulates expression of CCL2 in the intact and chemically injured hippocampus.

Expression of the chemokine (C-C motif) ligand 2 (CCL2), also known as, monocyte chemoattractant protein (MCP)-1, increases in response to disease-, trauma-, or toxicant-induced damage to the central nervous system (CNS). In the periphery, endogenous and exogenous glucocorticoids are known to suppress CCL2 expression associated with inflammatory conditions. However, such actions of glucocorticoids on CCL2 expression in the CNS remain unknown. Here, we explored the effects of the glucocorticoid, corticosterone (CORT), on the expression of CCL2 and its receptors, CCR2 and CCR5, in the hippocampal formation using intact, adrenalectomized (ADX) and trimethyltin (TMT)-treated rats. An immunosuppressive regimen of CORT did not alter the mRNA expression of CCL2 or its receptors in the hippocampus. ADX, however, markedly increased the expression of CCL2 and CCR2 mRNAs in the hippocampus, while CORT replacement reversed the effects of ADX on CCL2 gene expression. Hippocampal damage resulting from systemic administration of the organometallic neurotoxicant, TMT, was associated with microglial activation, as evidenced by enhanced expression of microglial markers integrin alphaM (CD11b) and F4/80, as well as, microglia-associated factors, CCL2 and IL-1alpha. An immunosuppressive dose of CORT, suppressed TMT-induced expression of CCL2. Given the association of CCL2 with microglial activation, it appears that CORT may play a role in regulating microglial activation. However, CORT treatment did not alter TMT-mediated neuronal damage and astrogliosis. Such observations suggest that injury-related expression of microglia-associated chemokines and cytokines may subserve a role unrelated to neuronal damage. In summary, our data indicate that in the CNS, CCL2 gene expression is under negative regulation by glucocorticoids.

Adrenalectomy↗

PubMed2004

Cytokines participate in neuronal death induced by trimethyltin in the rat hippocampus via type II glucocorticoid receptors.

We investigated the role of IL-1alpha and IL-1beta expressed in the reactive gliosis following hippocampal damage induced by trimethyltin (TMT). IL-1alpha immunoreactivity was expressed earlier in small glial cells on day 4 post-TMT, while IL-1beta expression was obvious in large swollen glial cells on day 14 post-TMT. Both IL-1alpha and IL-1beta immunoreactivities were double-labeled with astrocyte marker, vimentin, but not with a microglia marker, OX-42. The expression of both IL-1alpha/beta was enhanced by adrenalectomy (ADX) prior to TMT administration. Corticosterone (CORT) or dexamethasone (DEX) supplementation not only cancelled effects of ADX, but also partially reversed TMT-induced enhancement of IL-1alpha/beta expressions. These changes coincided with TMT-induced neuronal death in CA3 pyramidal cells of the hippocampus. It is suggested that IL-1alpha/beta expressed in reactive astrocytes participate in TMT neurotoxicity via type II glucocorticoid receptors.

Adrenalectomy↗

PubMed2005

Cytokines participate in neuronal death induced by trimethyltin in the rat hippocampus via type II glucocorticoid receptors.

Adrenalectomy↗

PubMed2006

Beneficial effects of FK506 for experimental temporal lobe epilepsy.

FK506, originally classified as an immunosuppressant, may also be implicated in some events in the central nervous system. FK506 elicits both neuroprotective and neurotrophic effects in vitro. FK506 is neuroprotective for focal cerebral ischemia, but it is not clear whether FK506 has neuroprotective effects for other brain diseases. In this study, we investigated possible neuroprotective effects of FK506 in experimental temporal lobe epilepsy (TLE) induced by kainic acid (KA) or trimethyltin (TMT). In rat models, we observed marked protection against seizures, abnormal behaviors, and accompanying delayed neuronal damage in the hippocampus by the systemic injection of FK506.

Aggression↗

PubMed2006

Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression.

The neurotoxic heavy metal trimethyltin (TMT) primarily damages neurons of the hippocampus and limbic areas of the temporal lobe, and causes a dose-dependent decrease in the polysialated form of the neural cell adhesion molecule (PSA-NCAM) in the mouse hippocampus. In the current study, we attempted to associate deficits in spatial learning following TMT exposure at various stages in learning with changes in levels of NCAM-180 and PSA-NCAM in both the hippocampus and frontal cortex. Mice were treated with TMT either before or after training on a spatial learning paradigm and examined for changes in NCAM and PSA-NCAM 12h later. In the first set of experiments, male BALB/c mice were injected with TMT (2.25 mg/kg) or saline i.p. and tested 24-168 h later using hidden and visible versions of the water maze, as well as light avoidance and motor activity. Mice in both treated and control groups which demonstrated a significant improvement in water maze performance also showed an elevation in hippocampal PSA-NCAM at all time points examined. TMT exposure impaired spatial learning and blocked learning-induced elevations in PSA-NCAM expression 24-96 h post-treatment, but these deficits disappeared by 168 h post-treatment. Mice exposed to TMT during reconsolidation of spatial learning (after repeated water maze training) demonstrated a mild and transient difference in escape latency compared to saline exposed mice. TMT administration during this period did not result in the attenuation of PSA-NCAM expression observed when animals were exposed before training. These results confirm a specific role for PSA-NCAM in acquisition and consolidation of spatial memory.

Animals↗

PubMed2004

In vivo activation of c-Jun N-terminal kinase signaling cascade prior to granule cell death induced by trimethyltin in the dentate gyrus of mice.

The systemic administration of trimethyltin (TMT, 2.8 mg/kg, i.p.) induced granule cell death in the mouse dentate gyrus selectively 2 days later. The administration of TMT not only enhanced activator protein-1 DNA binding, along with an increase in expression of c-Jun and Fra-2, in the hippocampus 1 day later, but also facilitated phosphorylation of c-Jun N-terminal kinase (JNK) within the cytosol and nucleus. There was also a concomitant increase in the level of phosphorylated JNK kinase (MKK4/SEK1) in the cytosol 16-24 h after the administration. Moreover, TMT markedly elevated endogenous levels of both phosphorylated c-Jun and phosphorylated activating transcription factor-2 (ATF-2), in addition to activating JNK activity in the nuclear extracts obtained 16-24 h post-administration. Immunohistochemical analysis revealed that whereas Fra-2 and phosphorylated ATF-2 were expressed in the CA1 pyramidal cell layer predominantly, phosphorylated c-Jun was observed in both the CA1 pyramidal and dentate granule cell layers after TMT administration. Taken together, our data indicate that TMT activates the JNK pathway in the hippocampus prior to neuronal cell death. The prior activation of this pathway could be at least in part involved in the TMT-induced neural damage seen in the dentate granule cells of mice.

Animals↗

PubMed2005

Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis.

The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.

Animals↗

PubMed2006

Vibrational spectra and ab initio analysis of tert-butyl, trimethylsilyl, trimethylgermyl, and trimethylstannyl derivatives of 3,3-dimethylcyclopropene VII. 3,3-Dimethyl-1-(trimethylstannyl) cyclopropene.

The quantum mechanical force fields (QMFF's) of 3,3-dimethyl-1-(tert-butyl)cyclopropene (I), 3,3-dimethyl-1-(trimethylsilyl)cyclopropene (II), 3,3-dimethyl-1-(trimethylgermyl)cyclopropene (III), and 3,3-dimethyl-1-(trimethylstannyl)cyclopropene (IV) were calculated at the HF/3-21G*//HF/3-21G* level. The set of scale factors for the correction of HF/3-21G*//HF/3-21G* QMFF of II was determined using its well-characterised vibrational spectrum. Transferral of the set of scale factors obtained for II to the QMFF's of I, III and IV and calculation of the fundamental frequencies resulted in good agreement between the calculated and previously assigned experimental frequencies of III. This again demonstrates the feasibility of transferral of a set of scale factors obtained for the correction of the QMFF of a molecule to others containing heteroatoms from the same column of the Mendeleyev Periodic Table. Thus the calculations performed permitted the accurate assignment of the fundamental vibrational frequencies in the experimental IR spectrum of IV. The vibrational frequencies of 3,3-dimethyl-1-(tert-butyl)cyclopropene (I) were also calculated from the HF/6-31G*//HF/6-31G* QMFF, scaled by the set of scale factors used previously for the HF/6-31G*//HF/6-31G* QMFF's of II and III. Regularities in the trends of some vibrational frequencies with increasing atomic number of the heteroatom are observed.

Algorithms↗