Abstract
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.
Highlights
The trisubstituted organotin compound trimethyltin chloride (TMT) is a potent neurotoxicant that causes, in mammalian brain, selective neuronal death localized in the limbic system and, in particular, in the hippocampus [1,2]
The consistency of microarray data largely depends on sample dimension and heterogeneity [109,110,111,112]. Such general observations perfectly apply to the case of microarray studies performed in the different TMT models that are characterized by relevant differences in the biological and technical features of the experimental protocols
The different models share data on the modulation of genes involved in the autophagic pathway, such as those encoding lysosomal enzymes [25,26,53], SNARE protein genes [25] and lipid biogenesis [27], suggesting a possible role played by this pathway in TMT-induced neuronal death
Summary
The trisubstituted organotin compound trimethyltin chloride (TMT) is a potent neurotoxicant that causes, in mammalian brain, selective neuronal death localized in the limbic system and, in particular, in the hippocampus [1,2]. The molecular mechanisms by which TMT induces selective neuronal death are still not conclusively clarified: different pathogenetic pathways, probably acting differently in in vivo and in vitro models, seem to be involved, including neuroinflammation, intracellular calcium overload, and oxidative stress [7,17,18]. The complete molecular scenario involved in TMT-induced neurodegeneration is still far from being clearly identified, though interesting insights have been obtained through genome-wide technologies, such as microarray analysis, aimed at global comparative gene expression profiling. The aim of this review is to discuss and rationalize the state-of-the-art on gene expression profiling data regarding the TMT intoxication model, in order to identify comparable features that may allow focusing on significantly involved pathways
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