1-Methyl-4-Phenylpyridinium Induces Autocrine Excitotoxicity, Protease Activation, and Neuronal Apoptosis

Leist, Marcel; Volbracht, Christiane; Fava, Eugenio; Nicotera, Pierluigi

1-Methyl-4-Phenylpyridinium Induces Autocrine Excitotoxicity, Protease Activation, and Neuronal Apoptosis

Dateien

molpharmacol98.pdfGröße: 642.62 KBDownloads: 352

Datum

1998

Autor:innen

Leist, Marcel

Volbracht, Christiane

Fava, Eugenio

Nicotera, Pierluigi

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Molecular Pharmacology. 1998, 54(5), pp. 789-801. Available under: doi: 10.1124/mol.54.5.789

Zusammenfassung

The pathogenesis of several neurodegenerative diseases may involve indirect excitotoxic mechanisms, where glutamate receptor overstimulation is a secondary consequence of initial functional defects of neurons (e.g., impairment of mitochondrial energy generation). The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and other mitochondrial inhibitors (e.g., rotenone or 3-nitropropionic acid) elicited apoptosis in cerebellar granule cell cultures via stimulation of autocrine excitotoxicity. Cell death, increase in intracellular Ca2+ concentration, release of cytochrome c, and all biochemical and morphological signs of apoptosis were prevented by blockade of the N-methyl-D-aspartate receptor with noncompetitive, glycine-site or glutamate-site inhibitors. In addition, MPP+-induced apoptosis was reduced by high Mg2+ concentrations in the medium or by inhibiting exocytosis with clostridial neurotoxins. Two classes of cysteine proteases were involved in the execution of cell death: caspases and calpains. Inhibitors of either class of proteases prevented cell death, cleavage of intracellular proteins (i.e., fodrin), and the appearance of typical features of apoptosis such as phosphatidylserine translocation or DNA fragmentation. However, protease inhibitors did not interfere with the initial intracellular Ca2+ concentration increase. We suggest that MPP+ as well as other mitochondrial inhibitors trigger indirect excitotoxic processes, which lead to Ca2+ overload, protease activation, and subsequent neuronal apoptosis.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

LEIST, Marcel, Christiane VOLBRACHT, Eugenio FAVA, Pierluigi NICOTERA, 1998. 1-Methyl-4-Phenylpyridinium Induces Autocrine Excitotoxicity, Protease Activation, and Neuronal Apoptosis. In: Molecular Pharmacology. 1998, 54(5), pp. 789-801. Available under: doi: 10.1124/mol.54.5.789

BibTex

@article{Leist19981Meth-7833,
  year={1998},
  doi={10.1124/mol.54.5.789},
  title={1-Methyl-4-Phenylpyridinium Induces Autocrine Excitotoxicity, Protease Activation, and Neuronal Apoptosis},
  number={5},
  volume={54},
  journal={Molecular Pharmacology},
  pages={789--801},
  author={Leist, Marcel and Volbracht, Christiane and Fava, Eugenio and Nicotera, Pierluigi}
}

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