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Exposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction. [ABSTRACT FROM AUTHOR]

Chalice‐shaped tridentate poly‐Lewis acids (PLA) based on the tribenzotriquinacene (TBTQ) scaffold have been synthesised. Stannylation of the alkyne units, attached via phenyl‐spacers to the benzhydrylic positions to the TBTQ scaffold, with Me2NSnMe3 afforded the trimethyltin substituted TBTQ derivative. Replacement of these tin functions with other elements resulted in rigid boron‐ and aluminium‐functionalised PLAs. More flexible PLAs were obtained by hydrometallation reactions of the terminal alkyne groups of 4b,8b,12b‐tris((ethynyl)phenyl)tribenzotriquinacene. The resulting poly‐Lewis acids were tested for their acceptor abilities in host‐guest experiments with suitable bases. Preliminary tests with pyridine led to the synthesis of a large tridentate base with three pyridyl groups attached to a TBTQ backbone. Complexation of this Lewis base with the PLAs resulted in the formation of aggregates, which were studied in solution in more detail by 1H DOSY NMR experiments regarding their size. Further experiments were performed with the tridentate bases 1,4,7‐trimethyl‐1,4,7‐triazacyclononane and tris((dimethylphosphino)methyl)phenylsilane. [ABSTRACT FROM AUTHOR]

Objective: Trimethyltin (TMT) chloride is an organotin compound used in industry. It has been linked to generatingreactive oxygen species (ROS), inflammatory processes, and neuronal death. Carvacrol is a monoterpene phenolfound in the Lamiaceae plant family, modulating inflammatory conditions and necroptosis in neural tissue. This studyaimed to investigate the neuroprotective effects of carvacrol in a rat model of hippocampal neuronal injury inducedby TMT.Materials and Methods: In this experimental study, sixty male Wistar rats were randomly divided into five groups(n=12): group 1 receiving saline, group 2 received dimethyl sulfoxide (DMSO) as a vehicle for 21 days, group 3 receivinga single dose of TMT (8 mg/kg) and groups 4 and 5 receiving carvacrol 40 and 70 mg/kg daily for 21 days after a singledose of TMT. All injections were intraperitoneal (I.P.). Caspase-3, Bax, Bcl-2, and Bdnf gene expression and the numberof pyknotic neurons in the hippocampus were quantified. Spatial memory was assessed with a radial arm maze.Results: Statistical analysis of histological data revealed the carvacrol significantly attenuated cognitive dysfunction andthe number of pyknotic neurons in the hippocampal CA1 region of rats treated with TMT. Based on real-time polymerasechain reaction (PCR), carvacrol modulated the expression of genes involved in apoptosis (Bax and Caspase-3) andupregulated anti-apoptotic (Bcl-2) and brain derived neurotrophic factor (Bdnf) genes in the hippocampal tissue.Conclusion: These findings revealed neuroprotective effects of carvacrol which might be mediated by apoptotic andanti-apopetotic factors.

Objective: Trimethyltin (TMT) chloride is an organotin compound used in industry. It has been linked to generating reactive oxygen species (ROS), inflammatory processes, and neuronal death. Carvacrol is a monoterpene phenol found in the Lamiaceae plant family, modulating inflammatory conditions and necroptosis in neural tissue. This study aimed to investigate the neuroprotective effects of carvacrol in a rat model of hippocampal neuronal injury induced by TMT. Materials and Methods: In this experimental study, sixty male Wistar rats were randomly divided into five groups (n=12): group 1 receiving saline, group 2 received dimethyl sulfoxide (DMSO) as a vehicle for 21 days, group 3 receiving a single dose of TMT (8 mg/kg) and groups 4 and 5 receiving carvacrol 40 and 70 mg/kg daily for 21 days after a single dose of TMT. All injections were intraperitoneal (I.P.). Caspase-3, Bax, Bcl-2, and Bdnf gene expression and the number of pyknotic neurons in the hippocampus were quantified. Spatial memory was assessed with a radial arm maze. Results: Statistical analysis of histological data revealed the carvacrol significantly attenuated cognitive dysfunction and the number of pyknotic neurons in the hippocampal CA1 region of rats treated with TMT. Based on real-time polymerase chain reaction (PCR), carvacrol modulated the expression of genes involved in apoptosis (Bax and Caspase-3) and upregulated anti-apoptotic (Bcl-2) and brain derived neurotrophic factor (Bdnf) genes in the hippocampal tissue. Conclusion: These findings revealed neuroprotective effects of carvacrol which might be mediated by apoptotic and anti-apopetotic factors. [ABSTRACT FROM AUTHOR]

Spirulina (Spirulina platensis) and golden sea cucumber (Stichopus variegatus) are known to have antioxidant activity that has the potential to prevent neurodegeneration disease. The aim of this study was to examine the effect of the combination of spirulina and golden sea cucumber on Bcl2 gene expression in pyramidal hippocampus cells of trimethyltin-induced dementia (TMT) rats. The study used Sprague Dawley rats which were divided into six groups, namely the normal control group (CMC-Na and NaCl 0.9%), pain control (CMC-Na and TMT), positive control (citicoline dose 200 mg/kg BW and TMT) and and test control injected with TMT and given a combination of spirulina (S) and golden sea cucumber dose (G) with three ratios of SG-3:1, SG-1:1 and SG-1:3 in a single dose of 200 mg/kg BW. Sample and citicoline were given on days 1-28, while TMT injection was given a single dose of 8 mg/kg BW on day 8. On day 36, the rats were sacrificed, brains were removed and the right hemispherium cerebri was fed to 10% formalin in pbs. After 6 days, the hippocampus was separated for immunohistochemical observation. The test result data was statistically analyzed with a one-way ANOVA test then followed by post hoc tukey to see the differences between groups. Results showed the combination of spirulina and golden sea cucumber can increase the expression of the Bcl2 gene in the hippocampus. The combination of spirulina and golden sea cucumber (SG-1:3) at a dose of 200 mg/kg BW had the ability to increase Bcl2 expression almost the same as citicoline with the number of Bcl2 cell expressions being 27.51 ± 0.70 in the CA1 region and 69.96 ± 1.97 in the CA2-CA3 region. So, it can be concluded that SG-1:3 has the potential to prevent dementia.

A novel trimethyltin(IV) complex (Me3SnL), derived from 3-(4-methyl-2-oxoquinolin-1(2H)-yl)propanoate ligand, has been synthesized and characterized by elemental microanalysis, UV/Vis spectrophotometry, FT-IR and multinuclear (1H, 13C and 119Sn) NMR spectroscopies. Furthermore, the structure of the ligand precursor HL was solved using SC-XRD (single-crystal X-ray diffraction). The prediction of UV/Vis and NMR spectra by quantum-chemical methods was performed and compared to experimental findings. The protein binding affinity of Me3SnL towards BSA was determined by spectrofluorometric titration and subsequent molecular docking simulations. Me3SnL has been evaluated for its in vitro anticancer activity against three human cell lines, MCF-7 (breast adenocarcinoma), A375 (melanoma) and HCT116 (colorectal carcinoma), and three mouse tumor cell lines, 4T1 (breast carcinoma), B16 (melanoma) and CT26 (colon carcinoma), using MTT and CV assays. The strong inhibition of A375 cell proliferation, ROS/RNS upregulation and robust lipid peroxidation lead to autophagic cell death upon treatment with Me3SnL. [ABSTRACT FROM AUTHOR]

The endogenous regenerative capacity of the brain is quite weak; however, a regenerative reaction, the production of new neurons (neurogenesis), has been reported to occur in brain lesions. In addition, leukocytes are well known to infiltrate brain lesions. Therefore, leukocytes would also have a link with regenerative neurogenesis; however, their role has not been fully elucidated. In this study, we investigated leukocyte infiltration and its influence on brain tissue regeneration in a trimethyltin (TMT)‐injected mouse model of hippocampal regeneration. Immunohistochemically, CD3‐positive T lymphocytes were found in the hippocampal lesion of TMT‐injected mice. Prednisolone (PSL) treatment inhibited T lymphocyte infiltration and increased neuronal nuclei (NeuN)‐positive mature neurons and doublecortin (DCX)‐positive immature neurons in the hippocampus. Investigation of bromodeoxyuridine (BrdU)‐labeled newborn cells revealed the percentage of BrdU/NeuN‐ and BrdU/DCX‐positive cells increased by PSL treatment. These results indicate that infiltrated T lymphocytes prevent brain tissue regeneration by inhibiting hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

We have recently shown delayed increases in GABAB receptor (GABABR) subunit protein levels in the hippocampal dentate gyrus (DG), but not in the pyramidal CA1 and CA3 regions, at 15–30 days after the systemic single administration of trimethyltin (TMT) in mice. An attempt was thus made to determine whether the delayed increases return to the control levels found in naive mice afterward. In the DG on hippocampal slices obtained at 90 days after the administration, however, marked increases were still seen in protein levels of both GABABR1 and GABABR2 subunits without significant changes in calbindin and glial fibrillary acidic protein (GFAP) levels on immunoblotting analysis. Fluoro-Jade B staining clearly revealed the absence of degenerated neurons from the DG at 90 days after the administration. Although co-localization was invariably detected between GABABR2 subunit and GFAP in the DG at 30 days on immunohistochemical analysis, GABABR2-positive cells did not merge well with GFAP-positive cells in the DG at 90 days. These results suggest that both GABABR1 and GABABR2 subunits would be tardily and sustainably up-regulated by cells other than neurons and astrocytes in the murine DG at 90 days after a systemic single injection of TMT.

Exposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction.

Reliable fluid biomarkers for evaluating neurotoxicity have yet to be established. However, recent studies have reported neurofilament light chain as a fluid biomarker of several neurodegenerative disorders. In this study, we investigated changes in the cerebrospinal fluid and plasma levels of neurofilament light chain in mice treated with trimethyltin as a neurotoxicant. Trimethyltin diluted with saline was administered by intraperitoneal injection to mice at dose levels of 0 (vehicle control), 1.0, and 2.6 mg/kg body weight (dosage volume: 10 mL/kg). At 3 or 7 days after administration, animals were euthanized by exsanguination under 2–3% isoflurane inhalation anesthesia. Increased neurofilament light chain levels in both the cerebrospinal fluid and plasma were observed in animals from the trimethyltin 2.6 mg/kg body weight group, which indicated the brain lesions including neuronal cell death. Animals from the trimethyltin 1.0 mg/kg body weight group exhibited changes neither in neurofilament light chain levels in the cerebrospinal fluid and plasma nor in the histopathology of the brain at any time point. These data indicate that plasma neurofilament light chain can serve as a useful peripheral biomarker for detecting brain lesions such as neuronal necrosis in mice. [ABSTRACT FROM AUTHOR]

We investigated the neurological effects of the varied erinacine composition of different mycelia cultures in mice with trimethyltin (TMT)-induced neurodegeneration. Forty male ICR mice were randomly divided into five groups of Sham-veh, TMT-veh, TMT-EME, TMT-EMR and TMT-EME/R. The TMT groups received 2.6 mg/kg one-time intraperitoneal injections of TMT. Oral dosages of 200 mg/kg erinacine combination from each Hericium erinaceus mycelia (EM) cultivated formula (100% eucalyptus wood [E], 100% rubber wood [R], or 40% eucalyptus wood/60% rubber wood [E/R]) were given for two weeks. Spatial learning, memory, flexibility, and anxious behaviour were evaluated alongside brain tissues' oxidative status and histological analyses. Erinacine composition from EME/R exhibited significant positive effects on spatial learning, memory, flexibility, and anxiety (p < 0.05). These findings emerged concurrently with the significant mitigation of hippocampal lipid peroxidation, CA1 hippocampal, cortical neuron, and corpus callosum white matter degeneration (p < 0.05). These neurological benefits were associated with the EME/R composition of erinacine A, C, D, G, H, I, K and R. The best neuroprotective effect against TMT-induced neurodegeneration in mice is offered by the EME/R erinacine composition according to its anti-lipid peroxidation, its nurturing effect on neuronal and white matter, and mitigation of behavioural deficits. [ABSTRACT FROM AUTHOR]

Gastrointestinal symptoms are common health problems found during aging and neurodegenerative diseases. Trimethyltin-induced rat is known as an animal model of hippocampal degeneration with no data on enteric neurodegeneration. This study aimed to investigate the effect of trimethyltin (TMT) induction on the gastrointestinal tract. A 28-day animal study with male Sprague–Dawley rats (3 months old, 150–200 g) given a single TMT injection (8 mg/kg body weight, intraperitoneal) was conducted. The number of neurons in the colonic myenteric plexus was measured using stereological estimation. Histological scoring of colon inflammation, immunohistochemistry of tumor necrosis factor-α (TNF-α), and quantitative PCR were conducted. This study showed neuronal loss in the colonic myenteric plexus of TMT-induced rat model of neurodegeneration. Minor colon inflammation characterized by inflammatory cell infiltration and slightly higher expression of TNF-α in the colon mucosa were observed in the TMT-induced rat. However, the gut microbiota composition of the TMT-induced rat was not different from that of the control rats. This study demonstrates that TMT induces colonic myenteric plexus neurodegeneration and minor colon inflammation, which suggests the potential of this animal model to elucidate the communication between the gastrointestinal tract and central nervous system in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Purpose: Aromatic turmerone, a major constituent of turmeric oil, has been recently reported for proliferation of neural stem cell showing great potential for effective treatment in neurodegenerative disorders. However, its effect as oral brain targeted formulation for neuroprotection has not yet reported. The objective of the study was to investigate the pharmacokinetic of curcumin loaded turmeric oil microemulsion for brain targeting and probing the protective effect against trimethyltin induced neurodegeneration in adult zebrafish. Methods: Initially, in vivo plasma and brain pharmacokinetics was performed to determine improvement in relative bioavailability in rats followed by biodistribution and histopathological evaluation. Furthermore, the neuroprotective effect of the formulation was assessed in trimethyltin induced neurodegeneration model using adult zebrafish by behavioral analysis and biochemical analysis. Results: The in vivo plasma and brain pharmacokinetics showed 2-fold and 1.87-fold improvement respectively. Biodistribution study revealed significantly lower concentration in organs other than brain. Furthermore, curcumin microemulsion exhibited improved spatial memory by remembering the training and made correct choices after curcumin microemulsion treatment than other treatment groups. Histopathological evaluation confirmed neuroprotective effect on zebrafish brains. The biochemical analysis revealed reduced oxidative stress in curcumin microemulsion treated group. Conclusions: Overall results showed a great potential of curcumin microemulsion for brain targeting in the effective treatment of neurological ailments. [ABSTRACT FROM AUTHOR]

Abstract Background It has been demonstrated that reactive astrocytes can be polarized into pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype under neurotoxic and neurodegenerative conditions. Microglia have been suggested to play a critical role in astrocyte phenotype polarization by releasing pro- and anti-inflammatory mediators. In this study, we examined whether trimethyltin (TMT) insult can induce astrocyte polarization in the dentate gyrus of mice, and whether protein kinase Cδ (PKCδ) plays a role in TMT-induced astrocyte phenotype polarization. Methods Male C57BL/6 N mice received TMT (2.6 mg/kg, i.p.), and temporal changes in the mRNA expression of A1 and A2 phenotype markers were evaluated in the hippocampus. In addition, temporal and spatial changes in the protein expression of C3, S100A10, Iba-1, and p-PKCδ were examined in the dentate gyrus. Rottlerin (5 mg/kg, i.p. × 5 at 12-h intervals) was administered 3–5 days after TMT treatment, and the expression of A1 and A2 transcripts, p-PKCδ, Iba-1, C3, S100A10, and C1q was evaluated 6 days after TMT treatment. Results TMT treatment significantly increased the mRNA expression of A1 and A2 phenotype markers, and the increased expression of A1 markers remained longer than that of A2 markers. The immunoreactivity of the representative A1 phenotype marker, C3 and A2 phenotype marker, S100A10 peaked 6 days after TMT insult in the dentate gyrus. While C3 was expressed evenly throughout the dentate gyrus, S100A10 was highly expressed in the hilus and inner molecular layer. In addition, TMT insult induced microglial p-PKCδ expression. Treatment with rottlerin, a PKCδ inhibitor, decreased Iba-1 and C3 expression, but did not affect S100A10 expression, suggesting that PKCδ inhibition attenuates microglial activation and A1 astrocyte phenotype polarization. Consistently, rottlerin significantly reduced the expression of C1q and tumor necrosis factor-α (TNFα), which has been suggested to be released by activated microglia and induce A1 astrocyte polarization. Conclusion We demonstrated the temporal and spatial profiles of astrocyte polarization after TMT insult in the dentate gyrus of mice. Taken together, our results suggest that PKCδ plays a role in inducing A1 astrocyte polarization by promoting microglial activation and consequently increasing the expression of pro-inflammatory mediators after TMT insult.

Abstract Background Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice. Methods CD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20. Results Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system. Conclusions These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.

FLPs featuring aluminum–phosphane interactions, spring-loaded by a rigid biphenylene linker, have been accessed through a route where trimethyltin units at phosphane-functionalized organic backbones are exchanged by an AlCl2 moiety. Upon contact with substrates like CO2 these are readily bound by the Al/P site with release of strain. The system could also be utilized for a unique reactivity, namely the activation of allene. [ABSTRACT FROM AUTHOR]

Trimethyltin (TMT) is widely used as a major component of plastic stabilizers in agriculture and industry, and can accumulate in large quantities in the liver. To investigate the relationship between liver tissue damage induced by TMT exposure and YAP phosphorylation in mice, we gave the mice drinking water containing 0.01 mg/mL TMT for 14 days to establish an in vivo experimental model, and continuously treated AML12 cells with 20 μM TMT for 24 h to establish an in vitro experimental model. Transcriptomics revealed that TMT exposure altered 62,466 apparently diversely expressed genes, including 1197 upregulated and 899 downregulated genes, and that enrichment of the Hippo pathway occurred. Moreover, western blotting (WB) and quantitative real-time PCR (qRTPCR) results showed that TMT exposure triggered an increase in the expression of P-YAP, apoptosis and necroptosis-interrelated genes, and a decrease in Bcl-2 expression in mouse livers tissues and AML12 cells. The expression of P-YAP was significantly suppressed in the TRULI-treated TMT-exposed AML12 cells, while oxidative stress levels and damage were also significantly attenuated. In conclusion, TMT triggers YAP phosphorylation to induce oxidative stress inducing apoptosis and necroptosis in mouse livers tissues. Our results confirm the liver toxic effect and specific mechanism of TMT.

Trimethyltin (TMT) has been used as a cytotoxin to neurons rather than glial cells in the mammalian hippocampus. The systemic administration of TMT led to declined fluorescence of ZnAF-2 DA staining as a marker of intact mossy fibers and increased fluorescence of Fluoro-Jade B staining as a marker of degenerated neurons during the initial 2 to 5 days after the administration with later ameliorations within 30 days in the hippocampal dentate gyrus (DG) and CA3 region in mice. On immunoblotting analysis, both GABABR1 and GABABR2 subunit levels increased during 15 to 30 days after TMT along with significant decreases in glutamatergic GluA1 and GluA2/3 receptor subunit levels during 2 to 7 days in the DG, but not in other hippocampal regions such as CA1 and CA3 regions. Immunohistochemical analysis revealed the constitutive and inducible expression of GABABR2 subunit in cells immunoreactive to an astrocytic marker as well as neuronal markers in the DG with the absence of neither GABABR1a nor GABABR1b subunit from cells positive to an astrocytic marker. These results suggest that both GABABR1 and GABABR2 subunits may be up-regulated in cells other than neurons and astroglia in the DG at a late stage of TMT intoxication in mice. [ABSTRACT FROM AUTHOR]

Ultrastructural studies of the hippocampus and the prefrontal cortex of rats were performed 7, 30, and 50 days after their damage by neurotoxicant trimethyltin chloride (TMT). Significant damage to neurons was observed in both brain structures. In the hippocampus, a large number of autophagosomes (0.9±0.1 per μm2) appeared in the soma of neurons, dendrites, and axons in 7 days after intoxication. In addition, we observed the appearance of hyperchromic neurons with abnormal structure of mitochondria. In the prefrontal cortex, damaged neurons also contained autophagosomes, but their number was significantly lower (0.3±0.1 per μm2). The number of autophagosomes decreased with increasing the time after TMT administration: 30 days after injection, the content of autophagosomes in the hippocampus was 0.10±0.01 per μm2, while in the prefrontal cortex, autophagosomes were no longer found. We hypothesized that autophagy in the hippocampus was not effective enough to prevent neuronal death caused by the neurotoxicant. [ABSTRACT FROM AUTHOR]

As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner. The astrocyte algorithm was created using a commercial supervised deep learning platform and the used training set consisted of 940 astrocytes manually annotated from hippocampus and cortex. Glial fibrillary acidic protein-labeled brain sections of rat TMT model were analyzed for astrocytes with the trained algorithm. Algorithm was able to count the number of individual cells, cell areas, and circumferences. The astrocyte algorithm identified astrocytes with varying sizes from immunostained sections with high confidence. Algorithm analysis data revealed a novel morphometric marker based on cell area and circumference. This marker correlated with the time-dependent progression of the neurotoxic profile of TMT. This study highlights the potential of using novel deep learning-based image analysis tools in neurotoxicity and pharmacology studies. [ABSTRACT FROM AUTHOR]

Objective: In this study, we investigated sex- and region-specific effects of acute trimethyltin (TMT) exposure on mitochondrial biogenesis. Methods: We treated TMT to primary neuronal cultures and 4-week-old male and female mice. We measured the mitochondrial DNA copy numbers using the quantitative polymerase chain reaction method. We also measured mitochondrial biogenesis related genes (sirtuin-1, estrogen-related receptor alpha, cytochrome C oxidase subunit IV) by western blotting. Results: The mitochondrial DNA copy number increased in the primary hippocampal neuron; however, it decreased in the primary cortical neuron. The mitochondrial copy number increased in the hippocampus and decreased in the cortex in the TMT treated female mice, though the mitochondrial copy number increased in both cortex and hippocampus in the TMT treated male mice. TMT treatment increased sirtuin-1 expression in the male hippocampus but did not in the female brain. In the female brain, estrogen-related receptor alpha expression decreased in the cortex though there is no significant change in the male brain. The protein level of mitochondrial protein, cytochrome C oxidase subunit IV, increased in both cortex and hippocampus after TMT injection in male mice brain, but not in female mice brain. Conclusion: Our data suggest that acute TMT exposure induces distinct sex-specific metabolic characteristics in the brain before significant sexual maturation. [ABSTRACT FROM AUTHOR]

Sinomenine is the main bioactive ingredient of the medicinal plant Sinomenium acutum with neuroprotective potential. This study was designed to assess beneficial effect of sinomenine in alleviation of trimethyltin (TMT)-induced cognitive dysfunction. TMT was administered i.p. (8 mg/kg, once) and sinomenine was daily given p.o. 1 h after TMT for 3 weeks at doses of 25 or 100 mg/kg. Cognitive performance was assessed in various behavioral tests. In addition, oxidative stress- and inflammation-associated factors were measured and histochemical evaluation of the hippocampus was conducted. Sinomenine at a dose of 100 mg/kg significantly and partially increased discrimination index in novel object recognition (NOR), improved alternation in short-term Y maze, increased step-through latency in passive avoidance paradigm, and also reduced probe trial errors and latency in the Barnes maze task. Moreover, sinomenine somewhat prevented inappropriate hippocampal changes of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, nitrite, superoxide dismutase (SOD), tumor necrosis factor α (TNFα), interleukin 6 (IL 6), acetylcholinesterase (AChE) activity, beta secretase 1 (BACE 1) activity, and mitochondrial membrane potential (MMP) with no significant effect on glutathione (GSH), catalase, glutathione reductase, glutathione peroxidase, and myeloperoxidase (MPO). In addition, lower reactivity (IRA) for glial fibrillary acidic protein (GFAP) as an index of astrocyte activity was observed and loss of CA1 pyramidal neurons was attenuated following sinomenine treatment. This study demonstrated that sinomenine could lessen TMT-induced cognitive dysfunction which is partly due to its attenuation of hippocampal oxidative stress and neuroinflammation. [ABSTRACT FROM AUTHOR]

Trans-anethole is an aromatic compound that has been studied for its anti-inflammation, anticonvulsant, antinociceptive, and anticancer effects. A recent report found that trans-anethole exerted neuroprotective effects on the brain via multiple pathways. Since noxious stimuli may both induce neuronal cell injury and affect synaptic functions (e.g., synaptic transmission or plasticity), it is important to understand whether the neuroprotective effect of trans-anethole extends to synaptic plasticity. Here, the effects of trimethyltin (TMT), which is a neurotoxic organotin compound, was investigated using the field recording method on hippocampal slice of mice. The influence of trans-anethole on long-term potentiation (LTP) was also studied for both NMDA receptor-dependent and NMDA receptor–independent cases. The action of trans-anethole on TMT-induced LTP impairment was examined, too. These results revealed that trans-anethole enhances NMDA receptor-dependent and -independent LTP and alleviates TMT-induced LTP impairment. These results suggest that trans-anethole modulates hippocampal LTP induction, prompting us to speculate that it may be helpful for improving cognitive impairment arising from neurodegenerative diseases, including Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated that reactive astrocytes can be polarized into pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype under neurotoxic and neurodegenerative conditions. Microglia have been suggested to play a critical role in astrocyte phenotype polarization by releasing pro- and anti-inflammatory mediators. In this study, we examined whether trimethyltin (TMT) insult can induce astrocyte polarization in the dentate gyrus of mice, and whether protein kinase Cδ (PKCδ) plays a role in TMT-induced astrocyte phenotype polarization.Methods: Male C57BL/6 N mice received TMT (2.6 mg/kg, i.p.), and temporal changes in the mRNA expression of A1 and A2 phenotype markers were evaluated in the hippocampus. In addition, temporal and spatial changes in the protein expression of C3, S100A10, Iba-1, and p-PKCδ were examined in the dentate gyrus. Rottlerin (5 mg/kg, i.p. × 5 at 12-h intervals) was administered 3-5 days after TMT treatment, and the expression of A1 and A2 transcripts, p-PKCδ, Iba-1, C3, S100A10, and C1q was evaluated 6 days after TMT treatment.Results: TMT treatment significantly increased the mRNA expression of A1 and A2 phenotype markers, and the increased expression of A1 markers remained longer than that of A2 markers. The immunoreactivity of the representative A1 phenotype marker, C3 and A2 phenotype marker, S100A10 peaked 6 days after TMT insult in the dentate gyrus. While C3 was expressed evenly throughout the dentate gyrus, S100A10 was highly expressed in the hilus and inner molecular layer. In addition, TMT insult induced microglial p-PKCδ expression. Treatment with rottlerin, a PKCδ inhibitor, decreased Iba-1 and C3 expression, but did not affect S100A10 expression, suggesting that PKCδ inhibition attenuates microglial activation and A1 astrocyte phenotype polarization. Consistently, rottlerin significantly reduced the expression of C1q and tumor necrosis factor-α (TNFα), which has been suggested to be released by activated microglia and induce A1 astrocyte polarization.Conclusion: We demonstrated the temporal and spatial profiles of astrocyte polarization after TMT insult in the dentate gyrus of mice. Taken together, our results suggest that PKCδ plays a role in inducing A1 astrocyte polarization by promoting microglial activation and consequently increasing the expression of pro-inflammatory mediators after TMT insult. [ABSTRACT FROM AUTHOR]

Background: Trimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice.Methods: CD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after killing the mouse. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assay (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20.Results: Adoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time-lapse imaging in a Treg/microglia co-culture system.Conclusions: These data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Background & Objective: Alzheimer is a neurodegenerative disease in which numerous changes occur in the patient's brain, since it is suggested that royal jelly (RJ) and Physical activity have several pharmacological activities, including neuroprotective and improvement of cognitive function. This study aimed to investigate the effect of eight weeks of voluntary wheel running exercise with royal jelly consumption on behavioral disorders and antioxidant capacity in rats with Trimethytin model of Alzheimer’s disease. Materials & Methods: This experimental study was performed on 48 male rats; Alzheimer's Trimethytin was induced on 40 rats. The rats were then randomly divided into six groups each group consisting of 8 members: healthy control group (HC), Alzheimer control group (ADC), voluntary exercise (VW) (wheel running), sham (SH), voluntary exercise combined with the royal jelly intake (VWJ) and royal jelly intake (RJ). Voluntary wheel running was done for eight weeks, three sessions per week and 60 minutes each session. To determine depression and anxiety, The Forced Swimming Test (FST) and Elevated Plus-Maze (EPM) were used respectively. Real-Time PCR was used to determine Gene expression of Superoxide dismutase (SOD) and Glutathione peroxidase (GPX). Data analysis was performed by the multivariate analysis of variance (MANOVA) test and post hoc Scheffe at the significance level of P

Trimethyltin chloride (TMT) is a stabilizer for polyvinyl chloride plastics that causes serious health hazards in nontarget organisms. Melatonin (MT) exhibits powerful protective effects in cardiac diseases. As a new environmental pollutant, TMT‐induced cardiotoxicity and the protective effects of MT remain unclear. To explore this, the mice were treated with TMT (2.8 mg/kg) and/or MT (10 mg/kg) for 7 days. Firstly, the histopathological and ultrastructural evaluation showed that TMT induced cardiac damage, tumescent rupture and nuclear pyknosis. Moreover, TMT elevated the expressions of pyroptosis genes NLRP3, ASC and Cas1 and inflammation factors IL‐6, IL‐17 and TNFα. Secondly, TMT reduced antioxidant enzymes (GSH, CAT and T‐AOC) via decreasing the expression of genes associated with the Keap1‐Nrf2/ARE pathway to increase oxidative stress. Thirdly, TMT decreased the expression of genes associated with the ARE‐driven drug metabolizing enzymes (DMEs), including Akr7a3, Akr1b8, and Akr1b10. Besides, TMT upregulated the mRNA expression of nuclear Xenobiotic metabolism on cytochrome P450s enzymes via increasing the expression of CAR, PXP, and AHR genes. Furthermore, MT treatment mitigated the aforementioned adverse changes induced by TMT. Overall, these results demonstrated that TMT caused pyroptosis and inflammation to aggravate cardiac damage via inducing excessive oxidative stress, imbalance of DMEs homeostasis, and nuclear Xenobiotic metabolism disorder, which could be alleviated by MT. [ABSTRACT FROM AUTHOR]

Introduction: endurance and resistance exercise and the consumption of hawthorn alone and in combination have an effect on Alzheimer's disease. This study was conducted with the aim of the effect of hawthorn consumption and exercise on the inflammatory indices of Alzheimer's rats by trimethyltin chloride (TMT). Materials and methods: rats were randomly divided into 9 healthy control and Alzheimer's groups with interventions (control, endurance training, resistance training, combined training, hawthorn, endurance training + hawthorn, resistance training + hawthorn, combined training hawthorn). Then Alzheimer's disease developed. performed resistance, combined, endurance exercises every week (12 weeks). Finally, blood was taken from the inferior vena and the inflammatory variables CRP, IL-6, TNF-α were measured by ELISA method. The Shapiro-Wilk test was used to check the normal distribution of the data, and the one-way analysis of variance (ANOVA) was used to check the mean difference between the groups (Tukey's test). P <0.05 were considered statistically significant. Results: results showed that the induction of Alzheimer's disease induced by TMT caused a significant increase in the levels of TNF α, IL 6, CRP in the Alzheimer's control group compared to the healthy control. And 12 weeks of combined training with and without hawthorn had a significant decrease in the level of these variables compared to Alzheimer's control. Conclusion: As a result, endurance and resistance sports along with the consumption of hawthorn lead to the reduction of some inflammatory factors in Alzheimer's rats. [ABSTRACT FROM AUTHOR]

Previously it was shown that for reduction of anxiety and stress of experimental animals, preventive handling seems to be one of the most effective methods. The present study was oriented on Na,K-ATPase, a key enzyme for maintaining proper concentrations of intracellular sodium and potassium ions. Malfunction of this enzyme has an essential role in the development of neurodegenerative diseases. It is known that this enzyme requires approximately 50% of the energy available to the brain. Therefore in the present study utilization of the energy source ATP by Na,K-ATPase in the frontal cerebral cortex, using the method of enzyme kinetics was investigated. As a model of neurodegeneration treatment with trimethyltin (TMT) was applied. Daily handling (10 min/day) of healthy rats and rats suffering neurodegeneration induced by administration of TMT in a dose of (7.5 mg/kg), at postnatal days 60–102 altered the expression of catalytic subunits of Na,K-ATPase as well as kinetic properties of this enzyme in the frontal cerebral cortex of adult male Wistar rats. In addition to the previously published beneficial effect on spatial memory, daily treatment of rats was accompanied by improved maintenance of sodium homeostasis in the frontal cortex. The key system responsible for this process, Na,K-ATPase, was able to utilize better the energy substrate ATP. In rats, manipulation of TMT-induced neurodegeneration promoted the expression of the α2 isoform of the enzyme, which is typical for glial cells. In healthy rats, manipulation was followed by increased expression of the α3 subunit, which is typical of neurons. [ABSTRACT FROM AUTHOR]

Background. The direct or indirect effect of chemicals on the nervous system of humans or animals is referred to as neurotoxicity. Trimethyltin chloride (TMT) intoxication causes behavioral and cognitive deficiencies in humans and experimental animals. TMT has long been used as a model toxicant in the study of central nervous system (CNS) toxicity. Momordica charantia, which is used in traditional herbal medicine, has a variety of pharmacological functions. Mesoporous silica nanoparticles have a higher loading capacity, are less dense, and have a larger specific area. Objectives. To investigate a possible nanotherapy for Alzheimer's disease caused by trimethyltin chloride in freshwater zebrafish. Methods. An aqueous extract of M.charantia was used to perform the primary and secondary screening. The DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay was used to determine the antioxidant capacity of crude aqueous extracts of M. charantia. Mesoporous silica nanoparticles are made using a CTAB surfactant chemical process and tetraethyl orthosilicate. UV-Vis spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscope, and EDAX were used to characterize it. Danio rerio was used to test the trimethyltin chloride for Alzheimer's disease. The M. charantia and mesoporous silica nanoparticles were then tested in the same method. Results. The extract has no adverse effects on zebrafish, indicating that M. charantia is safe for human consumption. The histopathological findings indicate that the tissues of the fish infected with the extract had no pathological modifications. Conclusion. The M. charantia showed higher antioxidant activity and anticholinesterase activity, and upon further characterization and assessment, this could be a safe and potential drug candidate for Neurotoxicity. [ABSTRACT FROM AUTHOR]

• "In vivo neuropathology" is an imaging protocol that can identify sites of neuroinflammation across the entire brain. • This non-invasive imaging protocol allows studies on time-dependent neuropathology. • The global maps of neurotoxic injury can be used to guide the histopathology during preclinical drug development. • Analysis is achieved with a minimum number of rats in compliance with the humane care and use of laboratory animals. • "In vivo neuropathology" provides an alternative to the traditional tests for assessing drug neurotoxicity. • "In vivo neuropathology" can minimize the cost of preclinical CNS toxicology. Presented is a diffusion weighted imaging protocol with measures of apparent diffusion coefficient which when registered to a 3D MRI rat brain atlas provides site-specific information on 173 different brain areas. This protocol coined "in vivo neuropathology" was used to follow the progressive neurotoxic effects of trimethyltin on global gray matter microarchitecture. Four rats were given an IP injection of 7 mg/kg of the neurotoxin trimethyltin and imaged for changes in water diffusivity at 3- and 7-days post injections. At 3 days, there was a significant decrease in apparent diffusion coefficient, a proxy for cytotoxic edema, in several cortical areas and cerebellum. At 7 days the level of injury expanded to include most of the cerebral cortex, hippocampus, olfactory system, and cerebellum/brainstem corroborating much of the work done with traditional histopathology. Analysis is achieved with a minimum number of rats adhering to the laws and regulations around the humane care and use of laboratory animals, providing an alternative to the traditional tests for assessing drug neurotoxicity. "In vivo neuropathology" can minimize the cost, expedite the process, and identify subtle changes in site-specific brain microarchitecture across the entire brain. [ABSTRACT FROM AUTHOR]

The present study investigated the neural health benefit of beta-sitosterol (BSS) against trimethyltin (TMT)-induced neurodegeneration in mice. Forty male ICR mice were randomly divided into Sham-veh, TMT-veh, TMT-BSS50, and TMT-BSS100. A one-time intraperitoneal injection of 2.6 mg/kg of TMT was given to mice in TMT groups. Vehicle (veh), BSS 50 mg/kg or BSS 100 mg/kg were orally given for 2 weeks. Spatial learning and memory were evaluated. Brain oxidative status, hippocampal neuropathology, and reactive astrocytes were done. White matter pathology was also evaluated. The results indicated the massy effect of TMT on induced motor ability and spatial memory deficits in accordance with increased neuronal degeneration in CA1, CA3, and DG and internal capsule white matter damage. TMT also induced the reduction of reactive astrocytes in CA1 and DG. Brain's catalase activity was significantly reduced by TMT, but not in mice with BSS treatments. Both doses of BSS treatment exhibited improvement in motor ability and spatial memory deficits in accordance with the activation of reactive astrocytes in CA1, CA3, and DG. However, they successfully prevented the increase of neuronal degeneration in CA1 found only with the BSS dose of 100 mg/kg, and it was indicated as the effective dose for neuroprotection in the vulnerable brain area. This study demonstrated mitigative effects of BSS against motor ability and memory deficits with neural health benefits, including a protective effect against CA1 neurodegeneration and a nurturing effect on hippocampal reactive astrocytes.

We have recently shown delayed increases in GABA B receptor (GABA B R) subunit protein levels in the hippocampal dentate gyrus (DG), but not in the pyramidal CA1 and CA3 regions, at 15-30 days after the systemic single administration of trimethyltin (TMT) in mice. An attempt was thus made to determine whether the delayed increases return to the control levels found in naive mice afterward. In the DG on hippocampal slices obtained at 90 days after the administration, however, marked increases were still seen in protein levels of both GABA B R1 and GABA B R2 subunits without significant changes in calbindin and glial fibrillary acidic protein (GFAP) levels on immunoblotting analysis. Fluoro-Jade B staining clearly revealed the absence of degenerated neurons from the DG at 90 days after the administration. Although co-localization was invariably detected between GABA B R2 subunit and GFAP in the DG at 30 days on immunohistochemical analysis, GABA B R2-positive cells did not merge well with GFAP-positive cells in the DG at 90 days. These results suggest that both GABA B R1 and GABA B R2 subunits would be tardily and sustainably up-regulated by cells other than neurons and astrocytes in the murine DG at 90 days after a systemic single injection of TMT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

The organotin, trimethyltin (TMT), is a highly toxic compound. In this study, silver-stained rat brain sections were qualitatively and quantitatively evaluated for degeneration after systemic treatment with TMT. Degenerated neurons were counted using image analysis methods available in the HALO image analysis software. Specific brain areas including the cortex, inferior and superior colliculus, and thalamus were quantitatively analyzed. Our results indicate extensive and widespread damage to the rat brain after systemic administration of TMT. Qualitative results suggest severe TMT-induced toxicity 3 and 7 days after the administration of TMT. Trimethyltin toxicity was greatest in the hippocampus, olfactory area, cerebellum, pons, mammillary nucleus, inferior and superior colliculus, hypoglossal nucleus, thalamus, and cerebellar Purkinje cells. Quantification showed that the optic layer of the superior colliculus exhibited significantly more degeneration compared to layers above and below. The inferior colliculus showed greater degeneration in the dorsal area relative to the central area. Similarly, in cortical layers, there was greater neurodegeneration in deeper layers compared to superficial layers. Quantification of damage in various thalamic nuclei showed that the greatest degeneration occurred in midline and intralaminar nuclei. These results suggest selective neuronal network vulnerability to TMT-related toxicity in the rat brain. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trimethyltin chloride (TMT) exposure induced the alteration of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, the activity and expressions of Na+-K+-ATPase in hippocampus, medulla oblongata of mice and N2a cells. • After trimethyltin chloride exposure, there were significant changes in AMPK phosphorylation in hippocampus and medulla oblongata, which could lead to energy metabolism disorders. • Oxidative damage occurred in hippocampus and medulla oblongata of mice induced by TMT, further leading to decreased expression of PGC-1α. Trimethyltin chloride (TMT) is a by-product in the synthesis of organotin, a plastic stabilizer. With the rapid development of industry, the occupational hazards caused by TMT cannot be ignored. TMT is a typical neurotoxicant, which mainly damages the limbic system and brainstem of the nervous system. Previous studies have demonstrated that the neurotoxicity induced by TMT is linked to the inhibition of energy metabolism, but the underlying mechanism remains elusive. In order to investigate the mechanism of TMT-induced inhibition of energy metabolism, C57BL/6 male mice were administered by IP injection in different TMT doses (0 mg/kg, 1.00 mg/kg, 2.15 mg/kg and 4.64 mg/kg) and times (1d, 3d and 6d), and then the changes of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level and Na+-K+-ATPase activity in cerebral cortex, cerebellum, hippocampus, pons, medulla oblongata of mice, the expressions of Na+-K+-ATPase protein, AMP-activated protein kinase (AMPK), phosphorylated AMP-activated protein kinase(p-AMPK)and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) in hippocampus and medulla oblongata were measured; the effects of TMT on the viability, the activity of SOD, glutathione (GSH) and Na+-K+-ATPase, MDA level, and the expression of PGC-1α and Na+-K+-ATPase protein in N2a cells were measured by different TMT doses and times, in order to verify the experiments in vivo. Our results found that most of the mice showed depression, tremor, epilepsy, spasm and other symptoms after TMT exposure. Moreover, with the increase of TMT dose, the activity of Na+-K+-ATPase and the expressions of AMPK protein in the hippocampus and medulla oblongata of mice decreased, and the expressions of p-AMPK protein increased. Peroxidative damage was evident in hippocampus, medulla oblongata of mice and N2a cells, and the expression of PGC-1α and Na+-K+-ATPase protein was significantly down-regulated. Therefore, it is reasonable to believe that TMT-induced neurotoxic symptoms and inhibition of energy metabolism may be related to p-AMPK and down-regulation of PGC-1α in the hippocampus and medulla oblongata. [ABSTRACT FROM AUTHOR]

Complex 1 was synthesized by the reaction of 4-(4-hydroxynaphthylazo)-benzoic acid with trimethyltin(IV) chloride in anhydrous methanol using triethylamine as base while 2 was synthesized by the reaction of 3-(2-hydroxynaphthylazo)-benzoic acid with dibutyltin(IV) oxide in anhydrous toluene. The complexes were characterized by elemental analysis, IR, and multinuclear (1H, 13C, and 119Sn) NMR spectroscopy. The coordination behavior and geometries around tin in 1 and 2 were established by X-ray crystallography while geometries of the complexes in solution were determined by 119Sn-NMR spectroscopy. The polymeric 1 displayed slightly distorted trigonal bipyramidal geometry around the tin with the equatorial plane occupied by three methyl groups and the axial positions occupied by a carboxylate oxygen and a phenoxide oxygen of another ligand. The tetranuclear 2 exhibited a bis[dicarboxylatotetraorganodistannoxane] type structure with a non-centrosymmetric Sn2O4 core where the central Sn2O2 ring was connected to two exo-cyclic tin ions through μ3-oxo atoms. The coordination geometry around exo- and endo-cyclic tin ions was distorted octahedral and deformed square pyramidal, respectively. 119Sn NMR spectral study suggested four-coordinate tetrahedral 1 while six- and five-coordinate structures around exo- and endo-cyclic tin ions for 2 in solution. [ABSTRACT FROM AUTHOR]

Background: Trimethyltin (TMT) is a toxic agent that causes oxidative stress, a laboratory model for inducing hippocampal injuries. Pentoxifylline (PTX) inhibits phosphodiesterase, inflammation and oxidative stress. This study evaluated the neuroprotective effects of PTX on injuries induced by TMT in the hippocampus. Methods: Sixty male Wistar rats were divided into five groups of 12 each. Group 1 received normal saline while Group 2 received a single dose of TMT (8 mg/kg). The other four groups received TMT at 8 mg/kg plus 60, 100 or 120 mg/kg PTX twice daily for six consecutive days. The rats' working and reference memory were investigated, using radial arm maze tasks. At the end of the experiments, the rats' brains were removed and processed for histological study of the hippocampus. Results: The TMT treatment prolonged the four baited arms tasks (P<0.001), while the PTX treatment at 60, 100 or 120 mg/kg significantly reduced the effects of TMT on the spatial memory (P<0.01). The working and reference memory errors significantly increased in the TMT group compared to the controls (P<0.001) while the PTX treatment significantly reduced the TMT effect (P<0.001). Also, TMT increased the number of pyknotic cells in the hippocampus (P<0.001), while PTX significantly decreased the mean number of pyknotic cells (P<0.05). Conclusion: The findings suggest that PTX can protect against the memory deficit and deleterious effects on rat hippocampus induced by TMT neurotoxicity. Thus, PTX is likely to be a potential agent to prevent against the neurotoxicity induced by TMT. [ABSTRACT FROM AUTHOR]

Cell death (apoptosis) in the hippocampus is related to impaired memory functions. Gotu kola (Centella asiatica) contains asiatic acid and asiaticoside, which act as antioxidants and improve memory function. This study was intended to determine the effects of gotu kola extracts on Bcl-2 gene expression and spatial memory in rats with impaired memory functions due to trimethyltin (TMT) injection. The rats were subdivided into six groups, each group consisting of 10 animals. The normal group was given sodium carboxymethyl cellulose (CMC-Na); the TMT group was given CMC-Na; the positive group was given 200 mg/kg bw citicoline; the extract groups were given a variation of gotu kola extract at 100 (P100), 200 (P200), and 400 mg/kg bw (P400) doses, respectively. These treatments were conducted for 35 days. TMT was injected intraperitoneally on Day 8 of treatment at a dose of 8 mg/kg bw in all groups except the normal group. On Days 29-35, the Morris water maze (MWM) spatial memory test was conducted. The rats were sacrificed, and their hippocampi were taken for immunohistochemical observation of Bcl-2 gene expression. The results showed TMT injection could lower the spatial memory of rats in the MWM and cause apoptosis of the pyramidal cells of the hippocampus. Gotu kola extract at 100, 200 and 400 mg/kg bw could increase the percentage of time spent (duration) and frequency of rats staying in the target quadrant in the probe trial of the MWM and increase Bcl-2 gene expression in the pyramidal cells of the hippocampus. Overall, the results have confirmed that gotu kola extract has the potential to prevent hippocampal cell death and improve the spatial memory of rats injected by TMT. [ABSTRACT FROM AUTHOR]

Trimethyltin chloride (TMT) is widely used as a constituent of fungicides and plastic stabilizers in the industrial and agricultural fields, and is generally acknowledged to have potent neurotoxicity, especially in the hippocampus; however, the mechanism of induction of neurotoxicity by TMT remains elusive. Herein, we exposed Neuro-2a cells to different concentrations of TMT (2, 4, and 8 μM) for 24 h. Proteomic analysis, coupled with bioinformatics analysis, revealed the important role of macroautophagy/autophagy-lysosome machinery in TMT-induced neurotoxicity. Further analysis indicated significant impairment of autophagic flux by TMT via suppressed lysosomal function, such as by inhibiting lysosomal proteolysis and changing the lysosomal pH, thereby contributing to defects in autophagic clearance and subsequently leading to nerve cell death. Mechanistically, molecular interaction networks of Ingenuity Pathway Analysis identified a downregulated molecule, KIF5A (kinesin family member 5A), as a key target in TMT-impaired autophagic flux. TMT decreased KIF5A protein expression, disrupted the interaction between KIF5A and lysosome, and impaired lysosomal axonal transport. Moreover, Kif5a overexpression restored axonal transport, increased lysosomal dysfunction, and antagonized TMT-induced neurotoxicity in vitro. Importantly, in TMT-administered mice with seizure symptoms and histomorphological injury in the hippocampus, TMT inhibited KIF5A expression in the hippocampus. Gene transfer of Kif5a enhanced autophagic clearance in the hippocampus and alleviated TMT-induced neurotoxicity in vivo. Our results are the first to demonstrate KIF5A-dependent axonal transport deficiency to cause autophagic flux impairment via disturbance of lysosomal function in TMT-induced neurotoxicity; manipulation of KIF5A may be a therapeutic approach for antagonizing TMT-induced neurotoxicity. Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTB: actin beta; AGC: automatic gain control; ATG: autophagy-related; ATP6V0D1: ATPase H+ transporting lysosomal V0 subunit D1; ATP6V1E1: ATPase H+ transporting lysosomal V1 subunit E1; CA: cornu ammonis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; DCTN1: dynactin subunit 1; DG: dentate gyrus; DYNLL1: dynein light chain LC8-type 1; FBS: fetal bovine serum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IPA: Ingenuity Pathway Analysis; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIF5A: kinesin family member 5A; LAMP: lysosomal-associated membrane protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRM: parallel reaction monitoring; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SYP: synaptophysin; TAX1BP1: Tax1 binding protein 1; TMT: trimethyltin chloride; TUB: tubulin. [ABSTRACT FROM AUTHOR]

[Display omitted] • Azo- and azo-imino carboxylate containing organotin(IV) compounds were synthesized. • Dimeric and tetrameric organotin(IV) compounds were generated. • Spectral characterization of organotin(IV) compounds was accomplished. • Compound 1 exerted considerable antidiabetic efficacy. • The antioxidant activity of compound 2 is found to be significant. Two new trimethyltin(IV) complexes including dinuclear-[(H 2 O)Me 3 Sn- µ -OH-SnMe 3 (HL1)] (1) and tetranuclear-[(Me 3 Sn) 2 (HOMe)H 2 L2] 2 (2) were synthesized by the reaction of 2-[2-{8-oxoquinolin-5(8H)-ylidene}hydrazinyl]benzoic acid (H 2 L1) and 2-[{4-hydroxy-3-(4-hydroxy-3-carboxyphenyliminomethyl)phenylazo}]benzoic acid (H 4 L2), respectively with trimethyltin(IV) chloride. The complexes were characterized using sophisticated spectroscopic tools and single crystal X-ray crystallographic analysis. The structure of the complex 1 is dinuclear and is made up of two Me 3 Sn(IV) centres connected by a hydroxyl (µ -OH) group. The carboxylate group from the H 2 L1 ligand and a water molecule are each responsible for coordinating the terminal edges of the two distinct tin centres. In the structure of complex 2 , which is tetranuclear in nature, a cyclic loop containing two symmetry-related Me 3 Sn(IV) units is confined by the alternate carboxylate-O and phenoxide-O atoms from the two H 4 L2 ligands. The remaining carboxylate groups from H 4 L2 ligands are attached to the other two terminal symmetry-related Me 3 Sn(IV) units, which are further bound by the methanol-O atoms, thereby preventing extended molecular structure. According to Hirshfeld surface and DFT topological analysis, the weak noncovalent interactions involving H-bonding are substantially responsible for the molecular packing. According to the 119Sn-NMR spectra, the hydroxo-bridge bonds of 1 in the solid state break to form two dissimilar tetrahedral environment about two Sn(IV) units in solution. Whereas, in complex 2 , the phenolate-O-Sn bonds in the solid state break to form a trigonal bipyramidal and a tetrahedral geometries around Sn(IV) linked by the H 4 L2 ligand in the solution, as if the ligand H 4 L2 holds Me 3 Sn(IV) and Me 3 Sn(IV)(OMe) units by its two carboxylate hands. The study of antidiabetic activities of the synthesized compounds against α -glucosidase and α -amylase reveal that the ligand H 4 L2 and complex 1 have efficient α -amylase inhibitory characteristics. In addition, the results of antioxidant activities indicate that complex 2 possesses promising activity and thus could be employed as an excellent antioxidant. [ABSTRACT FROM AUTHOR]

Centella asiatica (L.) Urb. is a nootropic that has been used medicinally for centuries. The present study investigates the anti-dementia effect of an n-butanol extract of Centella asiatica in a mouse model of neurodegeneration caused by trimethyltin (TMT). Mice were administered Centella asiatica extract (150 and 540 mg/kg) or a reference drug, tacrine (2.1 mg/kg), daily for one week before TMT injection and during tests to analyse spatial short-term and spatial working memory. The treatment of mice with TMT caused deficits in short-term spatial working memory and decreased the number of pyramidal cells in the hippocampal CA1 and CA3 regions elucidated by Nissl staining at 28 d post-TMT treatment. The administration of Centella asiatica extract or tacrine significantly attenuated the behavioural and histochemical changes caused by TMT. These results suggest that Centella asiatica extract improved memory deficits partly by protecting hippocampal neurons from TMT-induced damage.

Background & Objective: Alzheimer is a neurodegenerative disease in which numerous changes occur in the patient's brain, since it is suggested that royal jelly (RJ) and Physical activity have several pharmacological activities, including neuroprotective and improvement of cognitive function. This study aimed to investigate the effect of eight weeks of voluntary wheel running exercise with royal jelly consumption on behavioral disorders and antioxidant capacity in rats with Trimethytin model of Alzheimer’s disease. Materials & Methods: This experimental study was performed on 48 male rats; Alzheimer's Trimethytin was induced on 40 rats. The rats were then randomly divided into six groups each group consisting of 8 members: healthy control group (HC), Alzheimer control group (ADC), voluntary exercise (VW) (wheel running), sham (SH), voluntary exercise combined with the royal jelly intake (VWJ) and royal jelly intake (RJ). Voluntary wheel running was done for eight weeks, three sessions per week and 60 minutes each session. To determine depression and anxiety, The Forced Swimming Test (FST) and Elevated Plus-Maze (EPM) were used respectively. Real-Time PCR was used to determine Gene expression of Superoxide dismutase (SOD) and Glutathione peroxidase (GPX). Data analysis was performed by the multivariate analysis of variance (MANOVA) test and post hoc Scheffe at the significance level of P <0.05 using SPSS software version 20. Results: The results of multivariate analysis of variance show that there is a significant difference in all five variables of OAT, SOD, GPX, OAE and immobility in at least one group. According to the results of Scheffe post hoc test the findings showed that immobility time decreased in the VWJ, RJ, HC groups. The anxiety related indices increased in VWJ, RJ, HC groups. Although the differences in SOD antioxidant index were not significant, Gene expression of GPX increased in VWJ and RJ groups. Conclusion: In this study, voluntary exercise alone did not reduce anxiety and depression, and this highlights the role of Royal Jelly in it, and the results with the effect size of 0.757 showed the greatest effect on reducing the depression index. It seems that the combination of voluntary exercise with royal jelly supplementation can modulate behavioral disorders and antioxidant capacity in rats with trimethylettin-induced Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Background/Aim: In this study, we investigated sex-specific effects of acute exposure to trimethyltin, a known neurotoxicant on metabolic steroids. Materials and Methods: We administered intraperitoneally 2.3 mg/kg trimethyltin to 4-week-old male mice and measured the levels of metabolic steroids 24 h after treatment. We also measured mRNA and protein levels of cytochrome P450 1B1 using real-time polymerase chain reaction and western blotting. Results: Cortisol levels in the cortex increased in both sexes following acute trimethyltin exposure. The estradiol levels decreased, and the 4-hydroxyestradiol levels increased only in females. We also observed increased cytochrome P450 1B1 mRNA and protein levels only in the female cortex. Conclusion: Acute trimethyltin exposure induces distinct sex-specific metabolic changes in the brain before significant sexual maturation. [ABSTRACT FROM AUTHOR]

Introduction: Simvastatin is reported to improve cognition and to slow down progression of Alzheimer's disease. Trimethyltin (TMT), an organotin compound with neurotoxicant effects, selectively damages limbic system, especially the hippocampus. Animals exposed to trimethyltin develop behavioral alterations (hyperactivity and aggression), cognitive impairment (memory loss and learning impairment) and spontaneous seizures. Simvastatin is a drug with neuroprotective effect. This study was done to assess the effect of simvastatin in prevention of cognitive deficits in trimethyltin-induced Alzheimer’s like model in the rat. Methods and Materials: In this experimental study, 40 male Wistar rats (200-250 g) were randomly divided into 5 groups: control, control treated with Simvastatin at dose of 30 mg/kg, TMT, TMT treated with Simvastatin at doses of 10 or 30 mg/kg. Five groups of animals, each consisting of 8 rats were tested by novel object recognition, Y maze, passive avoidance paradigm, and the Barnes maze. Trimethyltin was administered i.p. (8 mg/kg, once) and simvastatin was daily given p.o 1 h after TMT for 3 weeks at doses of 10 or 30 mg/kg. Cognitive performance was assessed in various behavioral tests. Results: Administration of simvastatin to TMT group at a dose of 30 mg/kg significantly and partially increased discrimination index in novel object recognition, improved alternation in short-term Y maze, increased step-through latency in passive avoidance paradigm, and also reduced probe trial errors and latency in the Barnes maze task. Conclusion: Our results suggested that simvastatin may be useful to prevent cognitive decline due to neurotoxicants such as TMT. [ABSTRACT FROM AUTHOR]