Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin.
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.
Piacentini
Roberto
R
Institute of Human Physiology, Medical School, Catholic University S. Cuore, Rome, Italy.
Gangitano
Carlo
C
Ceccariglia
Sabrina
S
Del Fà
Aurora
A
Azzena
Gian Battista
GB
Michetti
Fabrizio
F
Grassi
Claudio
C
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*
D014298:Trimethyltin Compounds; C046488:trimethyltin