title: Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin.
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. The present study was aimed at determining whether intracellular Ca(2+) homeostasis dysregulation is involved in the TMT-induced neurodegeneration and if intracellular Ca(2+)-buffering mechanisms may exert a protective action in this experimental model of neurodegeneration. In cultured rat hippocampal neurons, TMT produced time- and concentration-dependent [Ca(2+)](i) increases that were primarily due to Ca(2+) release from intracellular stores although Ca(2+) entry through Ca(v)1 channels also contributed to [Ca(2+)](i) increases in the early phase of TMT action. Cell pre-treatment with the Ca(2+) chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (2 muM) significantly reduced the TMT-induced neuronal death. Moreover, CR(+) neurons responded to TMT with smaller [Ca(2+)](i) increases. Collectively, these data suggest that the neurotoxic action of TMT is mediated by Ca(2+) 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 Ca(2+) overload.
authors.affiliation: Institute of Human Physiology, Medical School, Catholic University S. Cuore, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Piacentini
authors.forename: Carlo
authors.initials: C
authors.lastname: Gangitano
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ceccariglia
authors.forename: Aurora
authors.initials: A
authors.lastname: Del Fà
authors.forename: Gian Battista
authors.initials: GB
authors.lastname: Azzena
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Michetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D014298:Trimethyltin Compounds; C046488:trimethyltin