Journal
JOURNAL OF NEUROCHEMISTRY
Volume 105, Issue 6, Pages 2109-2121Publisher
WILEY
DOI: 10.1111/j.1471-4159.2008.05297.x
Keywords
calcium dyshomeostasis; calretinin; confocal calcium imaging; neurodegeneration; rat hippocampal neurons; trimethyltin
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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 Ca(v)1 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 mu M) 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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