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Vol. 54, Issue 5, 789-801, November 1998
Faculty of Biology, Chair of Molecular Toxicology,
University of Konstanz, D-78457 Konstanz, Germany
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.
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