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Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.

Trimethyltin (TMT) is an organotin compound known to produce significant and selective neuronal degeneration and reactive astrogliosis in the rodent central nervous system. Autophagy is the main cellular mechanism for degrading and recycling protein aggregates and damaged organelles, which in different stress conditions, such as starvation, generally improves cell survival. Autophagy is documented in several pathologic conditions, including neurodegenerative diseases. This study aimed to investigate the autophagy and apoptosis signaling pathways in hippocampal neurons of TMT-treated (Wistar) rats to explore molecular mechanisms involved in toxicant-induced neuronal injury. The microtubule-associated protein light chain (LC3, autophagosome marker) and sequestosome1 (SQSTM1/p62) (substrate of autophagy-mediated degradation) expressions were examined by Western blotting at different time points after intoxication. The results demonstrate that the LC3 II/I ratio significantly increased at 3 and 5 days, and that p62 levels significantly decreased at 7 and 14 days. Immunofluorescence images of LC3/neuronal nuclear antigen (NeuN) showed numerous strongly positive LC3 neurons throughout the hippocampus at 3 and 5 days. The terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay indicated an increase in apoptotic cells starting from 5 days after treatment. In order to clarify apoptotic pathway, immunofluorescence images of apoptosis-inducing factor (AIF)/NeuN did not show nuclear translocation of AIF in neurons. Increased expression of cleaved Caspase-3 was revealed at 5–14 days in all hippocampal regions by Western blotting and immunohistochemistry analyses. These data clearly demonstrate that TMT intoxication induces a marked increase in both autophagy and caspase-dependent apoptosis, and that autophagy occurring just before apoptosis could have a potential role in neuronal loss in this experimental model of neurodegeneration.

Reelin is an extracellular matrix glycoprotein involved in the modulation of synaptic plasticity and essential for the proper radial migration of cortical neurons during development and for the integration and positioning of dentate granular cell progenitors; its expression is down-regulated as brain maturation is completed. Trimethyltin (TMT) is a potent neurotoxicant which causes selective neuronal death mainly localised in the CA1-CA3/hilus hippocampal regions. In the present study we analysed the expression of reelin and the modulation of endogenous neurogenesis in the postnatal rat hippocampus during TMT-induced neurodegeneration (TMT 6 mg/kg). Our results show that TMT administration induces changes in the physiological postnatal decrease of reelin expression in the hippocampus of developing rats. In particular, quantitative analysis of reelin-positive cells evidenced, in TMT-treated animals, a persistent reelin expression in the stratum lacunosum moleculare of Cornu Ammonis and in the molecular layer of Dentate Gyrus. In addition, a significant decrease in the number of bromodeoxyuridine (BrdU)-labeled newly-generated cells was also detectable in the subgranular zone of P21 TMT-treated rats compared with P21 control animals; no differences between P28 TMT-treated rats and age-matched control group were observed. In addition the neuronal commitment of BrdU-positive cells appeared reduced in P21 TMT-treated rats compared with P28 TMT-treated animals. Thus TMT treatment, administrated during development, induces an early reduction of endogenous neurogenesis and influences the hippocampal pattern of reelin expression in a temporally and regionally specific manner, altering the physiological decrease of this protein.

Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 µg/2 µl, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-in

Trimethyltin chloride (TMT) is a neurotoxicant producing neuronal degeneration and reactive astrogliosis in the mammalian central nervous system, especially the hippocampus. A previous magnetic resonance imaging investigation in TMT-treated rats evidenced dilation of lateral ventricles, also suggesting alterations in blood-brain barrier permeability and brain edema. Aquaporin 4 (AQP4), a glial water channel protein expressed mainly in the nervous system, is considered a specific marker of vascular permeability and thought to play an important role in brain edema (conditions). We studied AQP4 expression in the hippocampus and cerebral cortex of TMT-treated rats in order to explore the molecular mechanisms involved in brain edema occurring in these experimental conditions. Real-time PCR and western blotting data showed significant up-regulation of both AQP4 mRNA and protein levels starting 14 days after TMT treatment in the hippocampus and cortex. Parallel immunofluorescence studies indicated intense astrogliosis and AQP4 immunoreactivity diffusely pronounced in the hippocampal and cortex areas starting 14 days after TMT intoxication. In order to study the effects of TMT on vascular integrity, double-label immunofluorescence experiments for rat immunoglobulin G (IgG) and rat endothelial cell antigen-1 (RECA-1) or neuronal nuclei (NeuN) (endothelial and neuronal markers respectively) were performed. The results indicated, at 21 and 35 days after treatment, the presence of rat IgG in paravasal parenchyma and in some neuronal cells of the hippocampus and cortex. The extravasated IgG staining was temporally correlated with over-expression of neuronal vascular endothelial growth factor (VEGF) and the active phosphorylated form of its neuronal receptor (VEGFR-2P), suggesting that these factors may cooperate in mediating vascular leakage.

Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways.

The selective vulnerability of specific neuronal subpopulations to trimethyltin (TMT), an organotin compound with neurotoxicant effects selectively involving the limbic system and especially marked in the hippocampus, makes it useful to obtain in vivo models of neurodegeneration associated with behavioural alterations, such as hyperactivity and aggression, cognitive impairment as well as temporal lobe epilepsy. TMT has been widely used to study neuronal and glial factors involved in selective neuronal death, as well as the molecular mechanisms leading to hippocampal neurodegeneration (including neuroinflammation, excitotoxicity, intracellular calcium overload, mitochondrial dysfunction and oxidative stress). It also offers a valuable instrument to study the cell-cell interactions and signalling pathways that modulate injury-induced neurogenesis, including the involvement of newly generated neurons in the possible repair processes. Since TMT appears to be a useful tool to damage the brain and study the various responses to damage, this review summarises current data from in vivo and in vitro studies on neuroprotective strategies to counteract TMT-induced neuronal death, that may be useful to elucidate the role of putative candidates for translational medical research on neurodegenerative diseases.

Trimethyltin (TMT) ia a neurotoxicant....

Trimethyltin (TMT), an organotin compound considered a useful tool to obtain an experimental model of neurodegeneration, exhibits neurotoxicant effects selectively localised in the limbic system and especially in the hippocampus, which are different in the rat and in mice. In the rat hippocampus, we investigated the expression of aldehyde 4-hydroxynonenal, a major bioactive marker of membrane lipid peroxidation, heat shock protein (HSP) 110/105 family members, markers of oxidative stress, and the neuroinflammatory marker cyclooxygenase-2 after TMT-intoxication at various time points after treatment. Our data show that TMT-induced neurodegeneration in the rat hippocampus is associated specifically with oxidative stress and lipid peroxidation, but not with HSP expression, indicating species-specific differences in the neurotoxicity of TMT between rats and mice.

In the nervous system, protease-activated receptors (PARs), which are activated by thrombin and other extracellular proteases, are expressed widely at both neuronal and glial levels and have been shown to be involved in several brain pathologies. As far as the glial receptors are concerned, previous experiments performed in rat hippocampus showed that expression of PAR-1, the prototypic member of the PAR family, increased in astrocytes both in vivo and in vitro following treatment with trimethyltin (TMT). TMT is an organotin compound that induces severe hippocampal neurodegeneration associated with astrocyte and microglia activation. In the present experiments, the authors extended their investigation to microglial cells. In particular, by 7 days following TMT intoxication in vivo, confocal immunofluorescence revealed an evident PAR-1-related specific immunoreactivity in OX-42-positive microglial cells of the CA3 and hilus hippocampal regions. In line with the in vivo results, when primary rat microglial cells were treated in vitro with TMT, a strong upregulation of PAR-1 was observed by immunocytochemistry and Western blot analysis. These data provide further evidence that PAR-1 may be involved in microglial response to brain damage.

Trimethyltin chloride (TMT) is known to produce neuronal damage in the rat hippocampus, especially in the CA1/CA3 subfields, together with reactive astrogliosis. Previous studies indicate that in cultured rat hippocampal neurons the Ca2 cytosolic increase induced by TMT is correlated with apoptotic cell death, although some molecular aspects of the hippocampal neurodegeneration induced by this neurotoxicant still remain to be clarified. Cathepsin D (Cat D) is a lysosomal aspartic protease involved in some neurodegenerative processes and also seems to play an important role in the processes that regulate apoptosis. We investigated the specific activity and cellular expression of Cat D in the rat hippocampus in vivo and in cultured organotypic rat hippocampal slices. The role of Cat D in cell death processes and the mechanisms controlling Cat D were also investigated. Cat D activity was assayed in hippocampus homogenates of control and TMT-treated rats. In order to visualize the distribution of Cat D immunoreactivity in the hippocampus, double-label immunofluorescence for Cat D and Neu N, GFAP, OX42 was performed. In addition, in order to clarify the possible relationship between Cat D activity, neuronal calcium overload and neuronal death processes, organotypic hippocampal cultures were also treated with a Cat D inhibitor (Pepstatin A) or Calpain inhibitor (Calpeptin) or an intracellular Ca2 chelator (BAPTA-AM) in the presence of TMT. TMT treatment in rat hippocampus induced high levels of Cat D activity both in vivo and in vitro, in glial cells and in CA3 neurons, where a marked TMT-induced neuronal loss also occurred. Cat D is actively involved in CA3 neuronal death and the protease increase is a calcium-Calpain dependent phenomenon

Trimethyltin (TMT), an organotin compound with neurotoxicant effects selectively localised in the limbic system and especially marked in the hippocampus, is considered a useful tool to obtain an experimental model of neurodegeneration. Animals exposed to TMT develop behavioural alterations (hyperactivity, aggression), cognitive impairment (memory loss and learning impairment) and spontaneous seizures. TMT induces selective neuronal death involving the granular neurons of the Fascia Dentata and the pyramidal cells of the Cornu Ammonis, with a different pattern of severity and extension according to the various species studied and the dosage schedule. TMT-induced neurodegenerative events are associated with the activation of astrocytes and microglial cells and with the upregulation of proinflammatory cytokines. While the mechanisms by which TMT induces neurodegeneration are still not understood, many hypotheses seem to suggest that neuronal damage could be largely dependent on calcium overload. This review summarizes current data from in vivo and in vitro studies of the neurotoxic effects of TMT, focusing on the hypotheses regarding the mechanisms leading to neuronal death induced by the toxin.

Nitric oxide (NO) and purinergic ionotropic receptors (P2X) mediate cellular events in the central nervous system (CNS) under physiological conditions as well as during pathological events, and they have been recently proposed to interact in mediating CNS response to injury (Viscomi et al. [2004] Neuroscience 123:393-404; Florenzano et al. [2008] Pflugers Arch. 452:622-644). Trimethyltin (TMT) is an organotin compound that generates neurotoxic effects, and it has been used in a model of neurodegenerative disease and memory dysfunction. TMT causes neuronal death and reactive gliosis primarily in the hippocampus and other limbic regions. In the present study, we examined the degenerative events and the expression of nitric oxide synthase (NOS) and P2X receptor subtypes (P2X(1,2,4,7)Rs) that were induced by TMT administration at different time points (3, 7, 14, and 21 days) by conventional and confocal microscopy and Western blotting. Massive glial activation and neuronal death in the CA1 and CA3 regions were observed after TMT treatment. In these areas, astrocytic P2X(2)R and neuronal NOS were temporarily enhanced in association with the progression of neuronal death. In the hippocampus, the physiological expression of P2X(1)R, P2X(4)R, and P2X(7)R was not modified by TMT. The present data demonstrate that, as in other neurodegenerative models, TMT-induced hippocampal degeneration is associated with nitrergic and purinergic activations. Nevertheless, at odds with previous data, in this model the two systems are active in segregated cell populations, namely, P2XR in astrocytes and NOS in neurons. Finally, the temporal relations between P2XR and NOS expression and neuronal degeneration suggest interactions between P2XR/NO signaling and cell survival

The present study investigates the survival and fate of neural stem cells/progenitor cells (NSC/NPCs) homografted into the hippocampus of rats treated with trimethyltin (TMT), a potent neurotoxicant considered a useful tool to obtain a well characterized model of neurodegeneration, to evaluate their possible role in the reparative mechanisms that accompany neurodegenerative events. NSC/NPCs expressing eGFP by lentivirus-mediated infection were stereotaxically grafted into the hippocampus of TMT-treated animals and controls. Two weeks after transplantation surviving NSC/NPCs were detectable in 60% of TMT-treated animals and 30% of controls, while 30 days after transplantation only 40% of TMT-treated animals showed surviving grafted cells, which were undetectable in controls. At both times investigated, while grafted NSC/NPCs differentiated into neurons or astrocytes could be observed in addition to undifferentiated NSC/ NPCs, we did not find evidence of structural integration of grafted cells into the main site of hippocampal lesion leading to appreciable repair.

The present study investigates the survival and fate of neural stem cells/progenitor cells (NSC/NPCs) homografted into the hippocampus of rats treated with trimethyltin (TMT), a potent neurotoxicant considered a useful tool to obtain a well characterized model of neurodegeneration, to evaluate their possible role in the reparative mechanisms that accompany neurodegenerative events. NSC/NPCs expressing eGFP by lentivirus-mediated infection were stereotaxically grafted into the hippocampus of TMT-treated animals and controls. Two weeks after transplantation surviving NSC/NPCs were detectable in 60% of TMT-treated animals and 30% of controls, while 30 days after transplantation only 40% of TMT-treated animals showed surviving grafted cells, which were undetectable in controls. At both times investigated, while grafted NSC/NPCs differentiated into neurons or astrocytes could be observed in addition to undifferentiated NSC/NPCs, we did not find evidence of structural integration of grafted cells into the main site of hippocampal lesion leading to appreciable repair.

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

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.

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.

Endothelial monocyte-activating polypeptide-II (EMAP-II), a novel cytokine with proinflammatory and antiangiogenic properties, has previously been shown to be expressed by activated monocytes/microglial cells in the rat brain and was therefore considered a useful marker to stage microglial activation in inflammatory lesions. The aim of the present immunohistochemical study was to investigate expression of EMAP-II in the rat hippocampus after intoxication with the organotin compound trimethyltin (TMT). Administration of this neurotoxicant is known to produce brain damage mainly affecting the hippocampal formation, with severe neuronal cell loss being observed predominantly in regions CA-1 and CA-3. The maximum severity of TMT-induced brain damage is observed 21 days after a single ip administration. In this well-characterized model of neurodegeneration, activated microglial cells have been described to occur mainly in the early stages of TMT-induced neurotoxicity. Following TMT intoxication, we observed a significant increase in EMAP-II(+) monocytes/microglial cells in the CA-1 and the CA-3 regions. The CA-2 region, however, was largely spared. While appearance of single EMAP-II(+) microglial cells was observed already after 5 days, EMAP-II immunoreactivity reached its maximum after 21 days and persisted in some of the rats up to 35 days. These findings show a close correlation to the temporal and spatial pattern of neuronal damage described in the rat hippocampus after TMT administration previously. Thus, upregulation of EMAP-II by activated monocytes/microglial cells may serve as a sensitive marker of neurotoxic lesions in the rat brain.

The neurotoxicant trimethyltin (TMT) induces massive neuronal loss in vivo in the hippocampus of rodents, accompanied by behavioral alterations. The present study investigates the pattern of cell death after in vivo administration of TMT to adult mice. In the granular cell layer of the Dentate Gyrus, TUNEL staining detected DNA fragmentation, and apoptotic bodies were also evident. In addition, a ladder pattern of internucleosomal DNA fragmentation was shown in agarose gel electrophoresis. We show that activated caspase-3, which is known to play a pivotal role in apoptotic processes, is clearly expressed by degenerating neurons. Inducible cyclooxygenase is also expressed at cytoplasmic level by degenerating granular neurons, suggesting that this enzyme may participate in TMT-induced neurodegeneration.

In the model of trimethyltin (TMT)-induced neurodegeneration in developing rat hippocampus, calretinin (CR)-immunoreactive neurons are selectively spared and even more numerous than in controls. We investigated the possibility of an additional synthesis of CR using RT-PCR. The amount of CR mRNA increased significantly after TMT treatment. CR mRNA production after TMT treatment could hypothetically be regarded as a compensatory phenomenon in developing rats.

The environmental contaminants trimethyltin (TMT) and triethyltin (TET) stimulated the spontaneous release of [3H]noradrenaline ([3H]NA) from hippocampal slices in a time- and concentration-dependent manner. TMT was the most potent compound, exhibiting an EC50 value 10-fold lower (3.8 ¿M) than that of TET (39.5 ¿M). Metal-evoked [3H]NA release did not increase in the absence of desipramine and was completely blocked by reserpine preincubation, indicating a vesicular origin of [3H]NA release but not a mechanism involving reversal of the transmitter transporter. The voltage-gated Na+ channel blocker tetrodotoxin (TTX) did not affect metal-evoked [3H]NA release. [3H]NA release elicited by TMT was partially extracellular Ca2+dependent, since it was significantly decreased in a Ca2+-free EGTA- containing medium, whereas TET induced an extracellular Ca2+-independent release of [3H]NA. Neither inhibitors of Ca2+entry through Na+/Ca2+exchanger and voltage-gated calcium channels, nor agents that interfere with Ca2+-mobilization from intracellular stores affected [3H]NA release induced by TMT. TET-evoked [3H]NA release was reduced by ruthenium red, which depletes mitochondrial Ca2+stores, but was not modified by caffeine and thapsigargin, which interfere with Ca2+-mobilization from endoplasmic reticulum. The fact that TET effect was also attenuated by DIDS, an inhibitor of anion exchange, indicates that the effect of TET on spontaneous [3H]NA release may be mediated by intracellular mobilization of Ca2+ from mitochondrial stores through a Cl- dependent mechanism. (C) 2000 Academic Press.

The inherent biochemical, anatomical and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly apparent that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radical production as measured by the fluorescent probe dichlorofluorescein. This article considers the thesis that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that excess production of free radicals may be common phenomena of neurotoxicity.

The inherent biochemical, anatomical and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly apparent that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radical production as measured by the fluorescent probe dichlorofluorescein. This article considers the thesis that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that excess production of free radicals may be common phenomena of neurotoxicity.

As detailed in previous reports, the major purpose of this work, is to study biochemical mechanisms responsible for the toxic effects of the organometal neurotoxin trimethyltin (TMT) on learning, in order to develop strategies for prevention or alleviation of toxicity. Trialkyltins are used as stabilizers for plastics, or as biocides for control of fungus, barnacles, bacteria and insects. These compounds are anti-fouling toxicants of specific interest to the Navy, because of potential of estuarine contamination from naval vessels, and as a danger to seamen on ships carrying paint containing these compounds, since desalinated water used on these vessels may become contaminated. These compounds are also of interest as a model treatments for study of learning/memory dysfunction resulting from exposure to other toxicants (e.g. other heavy metals, organic solvents), or arising from disease states. We study learning in an autoshaping task, in which rats learn to touch a lever to obtain food. Keywords: Toxins; Antifouling coatings.

As detailed in previous reports, the major purpose of this work, is to study biochemical mechanisms responsible for the toxic effects of the organometal neurotoxin trimethyltin (TMT) on learning, in order to develop strategies for prevention or alleviation of toxicity. Trialkyltins are used as stabilizers for plastics, or as biocides for control of fungus, barnacles, bacteria and insects. These compounds are anti-fouling toxicants of specific interest to the Navy, because of potential of estuarine contamination from naval vessels, and as a danger to seamen on ships carrying paint containing these compounds, since desalinated water used on these vessels may become contaminated. These compounds are also of interest as a model treatments for study of learning/memory dysfunction resulting from exposure to other toxicants (e.g. other heavy metals, organic solvents), or arising from disease states. We study learning in an autoshaping task, in which rats learn to touch a lever to obtain food. During the past year, three papers have been published.

The goal of this research is to discover mechanisms of cognitive enhancement in normal and impaired subjects. Effects of the organometal neurotoxin trimethyltin (TMT) on learning is studied in an autoshaping model, in which rats learn to touch a lever to obtain food. The specific neurotoxic effects of TMT were first observed after accidental exposure of two French chemical workers who experienced memory loss and seizures. Numerous investigations in rodents have confirmed that TMT, administered systemically, produces a relatively specific lesion in hippocampus and related olfactory cortical structures. These lesions are associated with impairments in learning and memory. An initial dose-response study of effects of TMT on autoshaping was completed. Studies showing that rats treated with TMT or a mixed ganglioside preparation (which was administered to determine a possible therapeutic effect in TMT-treated animals) have decreased concentrations of hippocampal glucocorticoid receptors, which may be related to cognitive repairments. A study of the effects of the alpha 2-noradrenergic receptor antagonist yohimbine on autoshapings was completed. This prototypical anxiogneic agent, which increases forebrain norepinephrine release, enhances autoshaping in low doses. Yohimbine also induced increased behavioral arousal, which may account for its effects on autoshaping. Autoshaping is highly dependent upon the deprivation state of the animal: more food deprived rats learn faster.

The major purpose of this work, is to study mechanisms responsible for the toxic effects of the organometal neurotoxin trimethyltin (TMT) on learning, in order to develop strategies for prevention or alleviation of toxicity. Trialkyltins are used as stabilizers for plastics, or as biocides for control of fungus, barnacles, bacteria and insects. Their toxic effects have been known for over 100 years. However, the specific neurotoxic effects of TMT were first observed after accidental exposure of two French chemical workers who experienced memory loss and seizures. Since then, numerous investigations in rodents have confirmed that TMT, administered systemically, produces a relatively specific lesion in hippocampus and related olfactory cortical structures. These lesions are associated with impairments in learning and memory as measured in a wide variety of tasks. Thus, as well as being an environmental anti-fouling toxicant of specific interest to the Navy, the compound may also be of interest as a model treatment for study of learning/memory dysfunction resulting from exposure to other toxicants (e.g. other heavy metals, organic solvents) or arising from disease states. We study learning in an autoshaping task, in which rats learn to touch a lever to obtain food.

The major purpose of this work, is to study mechanisms responsible for the toxic effects of the organometal neurotoxin trimethyltin (TMT) on learning, in order to develop strategies for prevention or alleviation of toxicity. Trialkyltins are used as stabilizers for plastics, or as biocides for control of fungus, barnacles, bacteria and insects. As well as being an environmental anti-fouling toxicant of specific interest to the Navy, these compounds may also be of interest as a model treatments for study of learning/ memory dysfunction resulting from exposure to other toxicants (e.g. other heavy metals, organic solvents), or arising from disease states. Rats treated with TMT or a mixed ganglioside preparation (which was administered to determine a possible therapeutic effect in TMT-treated animals) have decreased concentrations of hippocampal glucocorticoid receptors, which may be related to cognitive impairments. We have also done work with the opiate antagonist naloxone, a substance which has memory-enhancing properties in many assays, but have found that this substance actually impairs acquisition of autoshaped behavior, whether given before or after training sessions

Both biologically active and autoclaved sediments convert trimethyltin hydroxide to the volatile tetramethyltin. Larger amounts of tetramethyltin were formed in the bioactive sediments than in the sterile sediments. No volatile tin compounds were detected in the absence of trimethyltin hydroxide or from trimethyltin hydroxide in seawater or in seawater containing bentonite. The formation of tetramethyltin is slow, taking over 80 days at 16 deg C to reach a maximum. The extent of conversion, although significant, is not extensive. The formation of tetramethyltin occurs in estuarine sediments by both abiotic and biologically enhanced pathways. A redistribution mechanism accounts for at least the abiotic pathway and possibly both formation pathways., Published in Science, v213 p770-771, 14 Aug 1981.

Alpha-Phenylphosphonatotrimethyltin(IV), C9H1503PSn, forms colorless crystals. The structure was solved by the heavy atom method to an R value of 0.046 for the 2578 reflections collected at 138 + or - 2K on an Enraf-Nonius CAD/4 automatic diffractometer using MoK sub alpha radiation. The molecular units associate to form an infinite, one-dimensional polymer in which planar trimethyltin(IV) groups are axially-bridged by -O-P-O- linkages of the phenylphosphonate ligand to yield an almost perfect trigonal bipyramid at tin. The chains are linear at the tin atoms, but bent through a bite angle of 115.4(3) deg at phosphorus. The chains propogate helically through the crystal, and each phenylphosphonate P=O and P-OH group is hydrogen bonded, holding adjacent helicies, turning in opposite directions, into two-dimensional sheets. The phenyl groups point outward from the center of the propagating helicies, separating the sheets from one another. Tin atoms occupy two non-equivalent environments, alternating metal atoms forming either two short or two long bonds to oxygen., See also AD-A088 674.