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

• Published in: Journal of neurochemistry 2008-06, Vol.105 (6), p.2109-2121
• Main Authors: Piacentini, Roberto, Gangitano, Carlo, Ceccariglia, Sabrina, Fà, Aurora Del, Azzena, Gian Battista, Michetti, Fabrizio, Grassi, Claudio
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Biochemistry; Biological and medical sciences; Calcium; calcium dyshomeostasis; Calcium Signaling - drug effects; Calcium Signaling - physiology; calretinin; Cell Death - drug effects; Cell Death - physiology; Cell physiology; Cells, Cultured; confocal calcium imaging; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Hippocampus - drug effects; Hippocampus - physiology; Homeostasis - drug effects; Homeostasis - physiology; Injuries of the nervous system and the skull. Diseases due to physical agents; Intracellular Fluid - drug effects; Intracellular Fluid - metabolism; Intracellular Fluid - physiology; Medical sciences; Molecular and cellular biology; Nerve Degeneration - chemically induced; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; neurodegeneration; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; rat hippocampal neurons; Rats; Rats, Wistar; Rodents; Traumas. Diseases due to physical agents; trimethyltin; Trimethyltin Compounds - toxicity
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05297.x

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.