Peroxynitrite and Nitric Oxide Donors Induce Neuronal Apoptosis by Eliciting Autocrine Excitotoxicity

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1997
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Fava, Eugenio
Montecucco, Cesare
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European Journal of Neuroscience ; 9 (1997), 7. - pp. 1488-1498. - ISSN 0953-816X. - eISSN 1460-9568
Abstract
Endogenous generation of nitric oxide and its congeners, including peroxynitrite (ONOO-), has been implicated in the mechanism of neuron loss in neurodegenerative diseases. Accordingly, nitric oxide donors and ONOO-can elicit both apoptosis and necrosis in neuron cultures. Here we show that nitric oxide donors and ONOO- are each able to trigger apoptosis of mouse cerebellar granule cells by an excitotoxic mechanism requiring exocytosis and NMDA receptor-mediated intracellular Ca2+ overload. This conclusion is supported by the following findings. Apoptosis was induced by various nitric oxide donors or by direct addition of ONOO- to differentiated cerebellar granule cell cultures that were sensitive to NMDA toxicity, but not in cerebellar granule cells that did not display NMDA-induced cell death (i.e. early days in culture) or in various glial cell populations. Donors of ONOO- or nitric oxide stimulated a sustained increase in intracellular Ca2+, which was prevented by inhibitors of NMDA receptors, such as MK-801 and 5-phospho-aminovaleric acid, or by dampening neuronal electrical activity with high concentrations of extracellular Mg2+. Moreover, these treatments and the exposure of cerebellar granule cells in nominally Ca2+-free media prevented apoptotic cell death. Both the intracellular Ca2+ increase and apoptosis elicited by ONOO- or the nitric oxide donors were prevented by blocking exocytosis with tetanus toxin or botulinum neurotoxin C.
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570 Biosciences, Biology
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apoptosis,mouse,clostridial neurotoxins,peroxynitrite,NMDA receptor
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ISO 690LEIST, Marcel, Eugenio FAVA, Cesare MONTECUCCO, Pierluigi NICOTERA, 1997. Peroxynitrite and Nitric Oxide Donors Induce Neuronal Apoptosis by Eliciting Autocrine Excitotoxicity. In: European Journal of Neuroscience. 9(7), pp. 1488-1498. ISSN 0953-816X. eISSN 1460-9568. Available under: doi: 10.1111/j.1460-9568.1997.tb01503.x
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@article{Leist1997Perox-8264,
  year={1997},
  doi={10.1111/j.1460-9568.1997.tb01503.x},
  title={Peroxynitrite and Nitric Oxide Donors Induce Neuronal Apoptosis by Eliciting Autocrine Excitotoxicity},
  number={7},
  volume={9},
  issn={0953-816X},
  journal={European Journal of Neuroscience},
  pages={1488--1498},
  author={Leist, Marcel and Fava, Eugenio and Montecucco, Cesare and Nicotera, Pierluigi}
}
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