Cyclooxygenase-2 and Caspase 3 Expression in Trimethyltin-Induced Apoptosis in the Mouse Hippocampus

Geloso, Maria Concetta; Vercelli, Alessandro; Corvino, Valentina; Repici, Mariaelena; Boca, Manila; Haglid, Kenneth G.; Zelano, Giovanni; Michetti, Fabrizio

doi:10.1006/exnr.2002.7866

Cited by 58 publications

(48 citation statements)

References 26 publications

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“…As has been previously described, acute exposure of mice to TMT results in extensive damage to dentate granule cells (Reuhl et al, 1983), accompanied by early activation of glial cells (Bruccoleri et al, 1998;Eskes et al, 2003). The mechanism of neuronal death induced by TMT has been linked to apoptosis and necrosis (Bruccoleri and Harry, 2000;Fiedorowicz et al, 2001), inflammation (Bruccoleri et al, 1998;Harry and Lefebvre d'Hellencourt, 2003), and signaling via the cyclooxygenase pathway (Geloso et al, 2002). In addition to the characterization of hippocampal damage, recent work has demonstrated an early elevation of cell proliferation and expression of cell cycle genes within the hippocampus (McPherson et al, 2003) suggestive of injury-induced neurogenesis.…”

Section: Introductionmentioning

confidence: 84%

Trimethyltin-induced neurogenesis in the murine hippocampus

Harry¹,

McPherson²,

Wine³

et al. 2003

neurotox res

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Neurogenesis continues to occur in the mature rodent brain with one of the most prominent sources for new neurons being the subgranular layer (SGL) of the dentate gyrus (DG) in the hippocampus. A number of factors can stimulate this process including synaptic activity and injury. To determine if this process would occur upon a direct injury to the dentate region, we exposed young, 21 day old male CD-1 mice to the hippocampal toxicant, trimethyltin (TMT). An acute i.p. injection of TMT (2 mg/kg) produced extensive damage and loss of dentate granule neurons within 72 h. This active period of degeneration was accompanied by an increase in the generation of progenitor cells within the SGL as identified by BrdU uptake and Ki-67 immunostaining. As additional markers for neurogenesis, both nestin and doublecortin showed increased staining patterns within the blades of the dentate. In these young weanling mice, the level of proliferation was sufficient to significantly repopulate the dentate region by 4 weeks post-TMT, suggesting a high level of regenerative potential. Our data indicate a significant level of neurogenesis occurring during the active process of degeneration and in an environment of microglia activation. The TMT-induced injury offers a model system for further examination of the process of neurogenesis, neural adaptation, and the influence of inflammatory factors and glia interactions.

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Section: Introductionmentioning

confidence: 84%

Trimethyltin-induced neurogenesis in the murine hippocampus

Harry¹,

McPherson²,

Wine³

et al. 2003

neurotox res

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“…It is noteworthy that TMT-induced cell death has also been shown to be linked to the above mentioned mechanisms (Philbert et al 2000;Gunasekar et al 2001;Geloso et al 2002;Jenkins and Barone 2004;Misiti et al 2008). All above commented data are consistent with the possibility that hippocampal neuronal death is mediated by TMTinduced intracellular Ca 2+ overload activating apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies showed that TMT-induced cell death occurs mainly by apoptosis as demonstrated by the presence of DNA fragmentation and chromatin condensation in TMT-treated cells and also involves the activation of the caspase family, cysteine proteases and the pro-apoptotic genes Bcl-2 ( Thompson et al 1996;Fiedorowicz et al 2001;Figiel and Fiedorowicz 2002;Geloso et al 2002; Abstract Trimethyltin (TMT) intoxication is considered a suitable experimental model to study the molecular basis of selective hippocampal neurodegeneration as that occurring in several neurodegenerative diseases. We have previously shown that rat hippocampal neurons expressing the Ca 2+ -binding protein calretinin (CR) are spared by the neurotoxic action of TMT hypothetically owing to their ability to buffer intracellular Ca 2+ overload.…”

mentioning

confidence: 99%

“…the hippocampus and the entorhinal and transentorhinal cortices. For these reasons TMT intoxication is regarded as a suitable model of chronic neurodegeneration with cognitive impairment, while the neuropathological, neurochemical and neurobehavioural alterations that occur in vivo have been widely analyzed in rodents, as well as in human cases of accidental poisoning with TMT (Fortemps et al 1978;Brown et al 1979;Chang et al 1982;Noland et al 1982;Stanton et al 1991;Feldman et al 1993;Geloso et al 1997Geloso et al , 2002Gui-bin et al 2000;Harry and Lefebvre d'Hellencourt 2003;Lattanzi et al 2007;Yoo et al 2007). The molecular and cellular pathogenesis of TMT-induced neurodegeneration is believed to be a composite picture involving several steps.…”

mentioning

confidence: 99%

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Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

Piacentini

Gangitano

Ceccariglia

et al. 2008

Journal of Neurochemistry

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Trimethyltin (TMT) intoxication is considered a suitable experimental model to study the molecular basis of selective hippocampal neurodegeneration as that occurring in several neurodegenerative diseases. We have previously shown that rat hippocampal neurons expressing the Ca2+‐binding protein calretinin (CR) are spared by the neurotoxic action of TMT hypothetically owing to their ability to buffer intracellular Ca2+ overload. The present study was aimed at determining whether intracellular Ca2+ homeostasis dysregulation is involved in the TMT‐induced neurodegeneration and if intracellular Ca2+‐buffering mechanisms may exert a protective action in this experimental model of neurodegeneration. In cultured rat hippocampal neurons, TMT produced time‐ and concentration‐dependent [Ca2+]i increases that were primarily due to Ca2+ release from intracellular stores although Ca2+ entry through Cav1 channels also contributed to [Ca2+]i increases in the early phase of TMT action. Cell pre‐treatment with the Ca2+ chelator, 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid tetrakis(acetoxymethyl ester) (2 μM) significantly reduced the TMT‐induced neuronal death. Moreover, CR+ neurons responded to TMT with smaller [Ca2+]i increases. Collectively, these data suggest that the neurotoxic action of TMT is mediated by Ca2+ homeostasis dysregulation, and the resistance of hippocampal neurons to TMT (including CR+ neurons) is not homogeneous among different neuron populations and is related to their ability to buffer intracellular Ca2+ overload.

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“…The neuropathological and neurobehavioral alterations exerted in vivo have been widely analyzed in rodents and in human cases of accidental poisoning (Fortemps et al 1978;Brown et al 1979;Chang et al 1982;Noland et al 1982;Stanton et al 1991;Feldman et al 1993;Geloso et al 1997Geloso et al , 2002Gui-bin et al 2000;Harry and Lefebvre d'Hellencourt 2003). The molecular and cellular pathogenesis of TMTintoxication syndrome is believed to be a composite picture involving several steps, as TMT is able to affect multiple processes in sensitive cells.…”

mentioning

confidence: 99%

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

Lattanzi¹,

Bernardini²,

Gangitano³

et al. 2006

Journal of Neurochemistry

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To more clearly elucidate the complete network of molecular mechanisms induced by trimethyltin (TMT) toxicity, we used a homogeneous cell culture model represented by PC12 cells treated with 1 and 5 lmol/L TMT for 24 h. The gene expression profile was performed by microarray analysis, enabling us to identify 189 genes that were significantly modulated in treated cells, compared with controls. The main effects of TMT on gene expression seem to be related to the activation of metabolic processes (glycolysis and lipogenesis) along with cell death pathways, membrane remodeling and intracellular biomolecules trafficking. These alterations are triggered by the neurotoxicant earlier than a strong decrease in cell viability, which occurs at higher TMT concentrations or at later time points. Some aspects of the transcriptional modulation observed in this study resemble the gene activation known to occur during cell response to hypoxia. Other cell toxicants have also been reported to exert similar effects on gene expression. Therefore, our data help to delineate general basic adaptive mechanisms possibly shared by cells responding to different death-inducing noxae, such as TMT.

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Cyclooxygenase-2 and Caspase 3 Expression in Trimethyltin-Induced Apoptosis in the Mouse Hippocampus

Cited by 58 publications

References 26 publications

Trimethyltin-induced neurogenesis in the murine hippocampus

Trimethyltin-induced neurogenesis in the murine hippocampus

Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

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