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PubMed1998

Spatiotemporal changes in hippocampal NMDA receptor binding as a consequence of trimethyltin neurotoxicity in the rat.

In the present study we examined the presumable changes in the distribution of N-methyl-D-aspartate (NMDA) receptors in the hippocampus of rat exposed to a potent neurotoxic drug, trimethyltin (TMT). Using in vitro receptor binding autoradiography, [3H]MK801 labelling was determined at 7, 14, 21, 30 and 60 days after treatment with TMT (single dose of 8 mg/kg, i.p.) in various hippocampal areas thought to be affected by the neurotoxin. At 21-60 days after exposure, a decrease in receptor binding was observed in CA1 hippocampal subfield (10-20%, P< 0.05). A reduction in binding density also occurred in CA4/ CA3c, where labelling vanished completely at longer times. In the molecular layer (ML) of the dentate gyrus (DG), however, 16-37% (P<0.05) increase in receptor binding was found at 14-60 days postexposure. These results suggest that exposure to TMT leads to an altered topography of NMDA receptor density sites in the rat hippocampus. Dynamics of the reduction in receptor binding in CA4/CA3c and CA1 followed the development of the well-known degenerative effects induced by the neurotoxin. In contrast, the enhanced binding density in the ML of the DG may be a part of a mechanism of plastic response of granule cells to denervation/reinnervation.

Animals↗
PubMed1999

Cholinergic and serotonergic alterations in the rat hippocampus following trimethyltin exposure and fetal neural transplantation.

Trimethyltin (TMT) apart from causing cholinergic denervation of the hippocampus, damages the serotonergic inputs into the hippocampus as well. In the present study, fetal cholinergic and serotonergic rich neuronal populations from septal and raphe regions, respectively, were transplanted alone or in combination (as co-grafts) in the hippocampus of TMT exposed rats. Neurotransmitter receptor binding and neurotransmitter levels were assayed 6 months post-transplantation. Fetal septal transplants (rich in cholinergic neurons) significantly restored the deficits in cholinergic (muscarinic) receptor binding and acetylcholinesterase activity caused by TMT exposure. Raphe transplants (rich in serotonergic neurons) restored the deficit in serotonergic receptor binding and serotonin levels caused by TMT. Co-grafts of fetal raphe and septal neurons restored both the cholinergic (muscarinic) and serotonergic receptor functions. The results suggest that co-grafting technique could provide a better restoration of functional deficits when more than one type of neuronal population is damaged.

Acetylcholine↗
PubMed2000

Long-term induction of Fos-related antigen-2 after methamphetamine-, methylenedioxymethamphetamine-, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine- and trimethyltin-induced brain injury.

A long-term induction of Fos-related antigens has been shown in neurons after brain injury, suggesting that Fos-related antigens are involved in enhancing the transcription of genes related to the process of regeneration and repair. In the present study, we report that levels of Fos-related antigen-2 are elevated in several models of chemically induced brain injury. Trimethyltin, which causes degeneration of neurons primarily in the hippocampus and other limbic regions, results in a five-fold induction of Fos-related antigen-2 immunoreactivity in neurons in the pyramidal and dentate layers of the hippocampus starting at seven days post-treatment and persisting for 60days. Methamphetamine and methylenedioxymethamphetamine, agents which cause degeneration of dopaminergic nerve terminals in the striatum of the mouse, cause an increase in Fos-related antigen-2 immunoreactivity which begins at three days post-treatment and returns to basal levels by days 5 and 15, respectively. Treatment with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine elevated levels of Fos-related antigen-2 in the mouse striatum at three days post-treatment. This abbreviated time-course of Fos-related antigen-2 induction is consistent with less severe insult (terminal damage) relative to trimethyltin (cell death), but induction occurs during the period of regeneration and repair in both models. Dexfenfluramine, a non-neurotoxic amphetamine, does not induce Fos-related antigen-2 expression. Decreasing core temperature of the mouse, which blocks amphetamine-induced neurotoxicity, also blocks Fos-related antigen-2 induction. In summary, Fos-related antigen-2 is induced in models of both cell death and terminal degeneration, suggesting that this transcription factor may serve as a universal signal transduction molecule involved in the regulation of genes related to regeneration and repair in the CNS.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Chemically induced neuronal damage and gliosis: enhanced expression of the proinflammatory chemokine, monocyte chemoattractant protein (MCP)-1, without a corresponding increase in proinflammatory cytokines(1).

Enhanced expression of proinflammatory cytokines and chemokines has long been linked to neuronal and glial responses to brain injury. Indeed, inflammation in the brain has been associated with damage that stems from conditions as diverse as infection, multiple sclerosis, trauma, and excitotoxicity. In many of these brain injuries, disruption of the blood-brain barrier (BBB) may allow entry of blood-borne factors that contribute to, or serve as the basis of, brain inflammatory responses. Administration of trimethyltin (TMT) to the rat results in loss of hippocampal neurons and an ensuing gliosis without BBB compromise. We used the TMT damage model to discover the proinflammatory cytokines and chemokines that are expressed in response to neuronal injury. TMT caused pyramidal cell damage within 3 days and a substantial loss of these neurons by 21 days post dosing. Marked microglial activation and astrogliosis were evident over the same time period. The BBB remained intact despite the presence of multiple indicators of TMT-induced neuropathology. TMT caused large increases in whole hippocampal-derived monocyte chemoattractant protein (MCP)-1 mRNA (1,000%) by day 3 and in MCP-1 (300%) by day 7. The mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, cytokines normally expressed during the earliest stage of inflammation, were not increased up to 21 days post dosing. Lipopolysaccharide, used as a positive control, caused large inductions of cytokine mRNA in liver, as well as an increase in IL-1beta in hippocampus, but it did not result in the induction of astrogliosis. The data suggest that enhanced expression of the proinflammatory cytokines, TNF-alpha, IL-1beta and IL-6, is not required for neuronal and glial responses to injury and that MCP-1 may serve a signaling function in the damaged CNS that is distinct from its role in proinflammatory events.

Animals↗
PubMed1997

Alterations in hippocampal expression of SNAP-25, GAP-43, stannin and glial fibrillary acidic protein following mechanical and trimethyltin-induced injury in the rat.

A set of well-defined antisera against neuronal and glial proteins were used to characterize patterns of protein expression in rat hippocampus following transection of the fimbira-fornix and perforant pathways or after administration of the selective neurotoxicant trimethyltin (8 mg/kg, i.p.). SNAP-25 (synaptosomal protein, mol. wt 25,000) is a neuron-specific, developmentally regulated presynaptic protein, stannin is a protein enriched in cells sensitive to trimethyltin, and GAP-43 (growth-associated protein, mol. wt 43,000) is associated with axonal growth and regeneration. Glial fibrillary acidic protein is an astrocyte-specific intermediate filament protein and a marker for reactive gliosis. SNAP-25 immunoreactivity was altered following both neurotoxicant and mechanical injury. Three days after fimbria-fornix/perforant path lesions, there was a loss of SNAP-25 immunoreactivity in hippocampal efferent pathways and in the lesioned entorhinal cortex. By day 12, there was evidence of reinnervation of hippocampal subfields by SNAP-25-immunopositive commissural afferent fibers. On day 3, immunoblots showed the appearance of SNAP-25a, a developmental isoform produced by alternative splicing of nine amino acids in exon 5, in lesioned tissues. This isoform declined by day 12 and was not found in contralateral control hippocampus or non-lesioned brain regions. Stannin immunoreactivity was unchanged, while GAP-43 was prominent on day 12 post-lesion. Glial fibrillary acidic protein immunoreactivity indicated gliosis near the site of pathway transection. In contrast, trimethyltin induced a marked loss of stannin immunoreactivity in hippocampal neurons seven days after injection. Trimethyltin increased glial fibrillary acidic protein staining in the hippocampus and other damaged regions. SNAP-25 immunoreactivity was markedly increased in mossy fibers and other hippocampal fields seven days following trimethyltin. Immunoblot analysis showed that only the adult SNAP-25b isoform was expressed after trimethyltin intoxication. These data suggest that SNAP-25 is a useful marker for presynaptic damage. Furthermore, reexpression of developmental isoforms of SNAP-25a may precede functional reinnervation when the postsynaptic target remains intact.

Animals↗
PubMed1997

Trimethyltin syndrome as a hippocampal degeneration model: temporal changes and neurochemical features of seizure susceptibility and learning impairment.

The effects of trimethyltin on the hippocampus were investigated in terms of changes in histology, depth electroencephalography, learning acquisition and memory retention, choline acetyltransferase and neuropeptides, and seizure-induced c-fos messenger RNA expression. The results were as follows. (1) Morphologically, trimethyltin produced a progressive loss of hippocampal CA3 and CA4 pyramidal cells, starting from four days after peroral treatment with trimethyltin hydroxide (9 mg/kg), as described previously. (2) Neurophysiologically, the increased seizure susceptibility to pentylenetetrazol treatment reached a maximum at four days post-trimethyltin and then declined after five days post-trimethyltin. The maximal seizure susceptibility at four days post-trimethyltin was confirmed by the immediate and long-lasting appearance of spike discharge in the hippocampus. However, this was not verified by the expression of c-fos messenger RNA in the hippocampus, which was comparable between trimethyltin-treated and control rats. (3) Behaviorally, the time-courses of aggression and learning impairment were similar to that of the seizure susceptibility. (4) Neurochemically, trimethyltin treatment caused changes of neurochemical markers, which were manifested by the elevation of neuropeptide Y content in the entorhinal cortex, and of choline acetyltransferase in the hippocampal CA3 subfield. Trimethyltin may offer potential as a tool for investigations on the relationship between neuronal death in the hippocampus and the development of seizure susceptibility and learning impairment. Alterations in glucocorticoids, glutamate and neuropeptides may all contribute to the manifestation of the trimethyltin syndrome.

Animals↗
PubMed1999

Odor-induced fast waves in the dentate gyrus depend on a pathway through posterior cerebral cortex: effects of limbic lesions and trimethyltin.

Previous research has shown that the odor of a variety of organic solvents and of components of the anal scent gland excretions of various predators will elicit a burst of fast waves of about 20 Hz in the olfactory bulb, pyriform cortex, and dentate gyrus of the rat. The present experiments show that large lesions of the caudal cerebral cortex, involving particularly the entorhinal and subicular cortices and the angular bundle, abolish the olfactory fast wave response of the dentate gyrus, but not the similar response of the olfactory bulb. In confirmation of previous work, such a lesion also abolishes an average evoked response elicited in the dentate gyrus by electrical stimulation of the olfactory bulb. Systemic treatment with the neurotoxin trimethyltin abolished the olfactory fast wave response in the olfactory bulb and both the olfactory fast wave and the olfactory evoked potential in the dentate gyrus. Large lesions of the amygdala or the septal nuclei did not eliminate either the dentate olfactory evoked potential or the odor-induced dentate fast wave response. However, the septal lesion reduced the amplitude of both spontaneous and odor-induced dentate fast wave activity. It is suggested that olfactory stimuli elicit 20 Hz dentate fast waves via a pathway from the olfactory bulb through the entorhinal cortex and, further, that cholinergic interneurons in the dentate gyrus may be essential to the dentate fast wave response.

Amygdala↗
PubMed1998

Toxicokinetics of trimethyltin in four inbred strains of mice.

Sixteen week old male AKR/J, Balb/cByJ, C57B1/6J and DBA/2J mice received single i.p. injections of trimethyltin (TMT). The toxic effects were weight loss, hyperexcitability, tremor, clonic-tonic convulsion, posterior paresis and death. The minimum toxic dose was 1.8 mg/kg, for the AKR strain and 2.3 mg/kg for the other strains. The highest non-lethal dose was 2.7 mg/kg for the AKR, DBA/2 and C57B1/6 strains and 3.0 mg/kg for the Balb/c strain. Blood levels of TMT peaked within 1 h and declined with half-lives of approximately 1.5 days. Blood levels of TMT were lower in the C57B1/6 mice due to greater tissue binding of TMT in C57B1/6 mice. Some of the toxic endpoints showed different rank orders among the strains, leading us to conclude that more than one biological process is responsible for the acute toxic effects of TMT in mice.

Animals↗
PubMed1997

Correspondence between middle frequency auditory loss in vivo and outer hair cell shortening in vitro.

The aromatic hydrocarbon, toluene, has been reported to disrupt auditory system function both in occupational epidemiological and in laboratory animal investigations. This agent, along with several other organic solvents, impairs hearing preferentially at middle frequencies - a finding that distinguishes these agents from the traditional high frequency impairment observed with ototoxic drugs such as aminoglycoside antibiotics and cisplatin. Prior investigations performed in vivo have identified the outer hair cell as a probable target for toluene exposure. The purpose of this investigation was to determine directly whether outer hair cells isolated from the guinea pig cochlea show morphological alterations consistent with the toxic response seen in physiological studies with toluene exposure. The effect of toluene superfusion on outer hair cell shortening was assessed for cells harvested from different locations within the cochlea. Control studies included assessment of cell shortening among outer hair cells exposed to trimethyltin and cells exposed to benzene. Trimethyltin disrupts high frequency hearing preferentially and benzene does not produce hearing loss in vivo. Toluene at a concentration of 100 microM produced a marked shortening of outer hair cells although the effect was significantly greater among cells isolated from the apical half of the cochlea than from the basal half of the cochlea. By contrast, trimethyltin at the same concentration produced a preferential shortening among outer hair cells from the base of the cochlea. Benzene (100 microM) did not disrupt outer hair cell length of cells harvested from the apex. The results indicate that intrinsic features of outer hair cells contribute significantly to the site of ototoxic impairment observed in vivo for toluene.

Animals↗
PubMed2000

Long-term microglial and astroglial activation in the hippocampus of trimethyltin-intoxicated rat: stimulation of NGF and TrkA immunoreactivities in astroglia but not in microglia.

In the present study we investigated the microglial and astroglial response after trimethyltin (TMT) exposure over a prolonged period of time. Male Wistar rats were given a single dose of TMT (8 mg/kg, i.p.) and survived 4, 7, 21, 60 and 180 days after the administration of the toxin. Histochemistry (Griffonia simplicifolia lectin staining) and immunocytochemistry for GFAP were applied to identify micro- and astroglial cells, respectively. To assess the trophic response of glial cells (NGF and TrkA expression), single or double staining experiments were performed. In addition, the biochemical evaluation of GFAP and NGF were carried out at chosen timepoints using immunoblotting technique and ELISA, respectively. The main findings of our study were as follows. (1) A protracted activation of microglia (at least up to 2 months posttreatment). (2) A long-lasting expression of GFAP immunoreactivity (at least up to 6 months posttreatment) and a steady increase in GFAP content (at least up to 2 months posttreatment). (3) The appearance of enormously enlarged, round-shape astrocytes exclusively localized to CA1 and observed 2 months posttreatment. (4) The stimulation of NGF and TrkA expression in reactive astrocytes. (5) The strongest activation of micro- and astroglia coincided with the most prominent neurodegeneration in the hippocampus, i.e., in CA4/CA3c and CA1. It is tempting to assume that the activation of glial cells in the hippocampal areas particularly vulnerable to TMT may affect neuronal fate after neurotoxic insult.

Animals↗
PubMedDate not supplied

Trimethyltin-induced expression of neuropeptide Y Y2 receptors in rat dentate gyrus.

Trimethyltin (TMT) causes prominent neuronal damage and enhanced expression of neuropeptide Y in the hippocampus. We investigated expression of neuropeptide Y Y2 receptors after TMT intoxication. Markedly elevated (by 470%) concentrations of Y2 receptor mRNA were found in the suprapyramidal blade of the dentate granule cell layer after 5 days. Increases in the infrapyramidal blade were less prominent (by 198%). After 16 days, mRNA levels in both blades of the granule cell layer showed no significant difference from those in controls. Quantification of Y2 receptor-specific binding revealed no significant change at both 5 and 16 days after TMT intoxication. It is suggested, together with a previous report describing a similar increase of neuropeptide Y expression, that a transient expression of Y2 receptors in the dentate gyrus in the initial phase of TMT intoxication may be involved in mediating TMT-induced hippocampal damage.

Animals↗
PubMed2001

High-efficiency astatination of antibodies using N-iodosuccinimide as the oxidising agent in labelling of N-succinimidyl 3-(trimethylstannyl)benzoate.

Monoclonal antibodies C215, reactive with colorectal carcinomas, and MOv18, reactive with most of the ovarian carcinomas, were radiohalogenated with [211At]astatine. The radiohalogen was conjugate coupled to antibodies via the intermediate labelling reagent N-succinimidyl-3-(trimethylstannyl)benzoate (m-MeATE) in a two-step, single-pot reaction. Optimisation of the labelling of the reagent was achieved using N-iodosuccinimide, NIS, as the oxidising agent. The yields ranged from 69-95% in the labelling of 0.1-1.0 nmole of the m-MeATE precursor. Subsequent conjugation to antibodies resulted in yields of 58+/-7%. In vitro binding to tumour cells showed that the immunoreactivity of both antibodies was retained after astatine labelling.

Antibodies, Monoclonal↗
PubMedDate not supplied

Synthesis and biodistribution of 211At-labeled, biotinylated, and charge-modified poly-L-lysine: evaluation for use as an effector molecule in pretargeted intraperitoneal tumor therapy.

Poly-L-lysine (7, 21, and 204 kDa) has been evaluated as an effector carrier for use in pretargeted intraperitoneal tumor therapy. For the synthesis, the epsilon-amino groups on the poly-L-lysine were modified in three steps utilizing conjugate biotinylation with biotin amidocaproate N-hydroxysuccinimide ester (BANHS), conjugate radiolabeling with (211)At using the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE), and charge modification using succinic anhydride, resulting in an increase in the molecular weight of approximately 80% of the final product. The labeling of the m-MeATE reagent and subsequent conjugation of the polymer were highly efficient with overall radiochemical yields in the range of 60-70%. The in vitro avidin binding ability of the modified polymer was almost complete (90-95%), as determined by binding to avidin beads using a convenient filter tube assay. Following intraperitoneal (ip) injection in athymic mice, the 13 kDa polymer product was cleared mainly via the kidneys with fast kinetics (biological half-live T(b) approximately 2 h) and with low whole-body retention. The clearance of the 38 kDa polymer was distributed between kidneys and liver, and the 363 kDa polymer was mainly sequestered by the liver with a T(b) of 8 h. Increased tissue uptake in the thyroid, lungs, stomach, and spleen following the distribution of the large effector molecules (38 and 363 kDa) suggests that degradation of the polymers by the liver may release some of the label as free astatine/astatide.

Aminocaproates↗
PubMed1985

Synthesis of high specific activity [75Br]- and [77Br]bromperidol and tissue distribution studies in the rat.

A rapid synthesis of [75Br]- and [77Br]bromperidol with specific activity exceeding 10000 Ci/mmol is described in which a trimethylstannylated analogue of bromperidol is used as a substrate for regiospecific no-carrier-added radiobromination. 4-[4-[4-(Trimethylstannyl)phenyl]-4-hydroxypiperidino]-4'- fluorobutyrophenone was synthesized by the reaction of (trimethylstannyl)sodium with haloperidol and purified by preparative HPLC. Subsequent radiobromination with no-carrier-added 75Br- or 77Br- and in situ oxidation using H2O2/CH3COOH gave a corrected radiochemical yield of 35% with a 30-min preparation time. Tissue distribution studies in the rat show a rapid and prolonged uptake into the brain, liver, and kidneys and consistently low blood concentrations that differ quantitatively from previous studies using relatively low specific activity bromperidol. Potential clinical applications for this high specific activity radiobrominated neuroleptic are discussed.

Animals↗
PubMed2001

Stille couplings catalytic in tin: a "Sn-F" approach.

A new tin recycling method for Stille couplings catalytic in tin is reported. PMHS made hypercoordinate by KF((aq)) allows Me(3)SnH to be efficiently recycled during a Pd(0)-catalyzed hydrostannation/Stille cascade. Relative to previously disclosed protocols, reaction times are shorter and because this process is believed to proceed through a Me(3)SnF intermediate the hazards and problems associated with trimethyltins are also diminished.[reaction: see text]

Catalysis↗
PubMed1998

GM1 ganglioside potentiates trimethyltin-induced expression of interleukin-1 beta and the nerve growth factor in reactive astrocytes in the rat hippocampus: an immunocytochemical study.

This study demonstrates potentiation by GM1 ganglioside treatment of trimethyltin (TMT) induced reactivity of astrocytes, and the expression of astroglial interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) immunoreactivities in the rat hippocampus. GM1 treatment also results in an increase of the number of IL-1 beta and NGF immunoreactive astrocytes. Both the intensity of gliosis and stimulation of IL-1 beta and NGF expression in astrocytes mostly occurs in the regions of heaviest neurodegeneration in the hippocampus (CA4/CA3c and CA1). It is tempting to assume that enhancement of astroglial NGF expression by GM1 ganglioside may play a role in the protective action of GM1 against neurotoxic insult.

Animals↗
PubMed1995

Activation of protein kinase C by trimethyltin: relevance to neurotoxicity.

The differentiated PC12 cell neuronal model was used to determine the effect of trimethyltin (TMT) on protein kinase C (PKC). Cells treated with 5-20 microM TMT showed a partial and sustained PKC translocation within 30 min and persisted over a 24-h period. TMT treatment was accompanied by a low level of PKC down-regulation over 24 h, which was small compared with that produced by phorbol esters. Confocal imaging of differentiated PC12 cells showed that PKC translocates to the plasma membrane and the translocation is blocked by the PKC inhibitor chelerythrine (1 microM). Phorbol myristate-induced PKC down-regulation or inhibition with chelerythrine provided protection against TMT-induced cytotoxicity. It was concluded that TMT-induced PKC translocation and activation contribute to the cytotoxicity of TMT in differentiated PC12 cells.

Alkaloids↗