1-methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis

被引:132
作者
Leist, M [1 ]
Volbracht, C [1 ]
Fava, E [1 ]
Nicotera, P [1 ]
机构
[1] Univ Konstanz, Fac Biol, Dept Mol Toxicol, Chair Mol Toxicol, D-78457 Constance, Germany
关键词
D O I
10.1124/mol.54.5.789
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:789 / 801
页数:13
相关论文
共 39 条
  • [1] EXCITOTOXICITY INDUCED BY ENHANCED EXCITATORY NEUROTRANSMISSION IN CULTURED HIPPOCAMPAL PYRAMIDAL NEURONS
    ABELE, AE
    SCHOLZ, KP
    SCHOLZ, WK
    MILLER, RJ
    [J]. NEURON, 1990, 4 (03) : 413 - 419
  • [2] GLUTAMATE-INDUCED NEURONAL DEATH - A SUCCESSION OF NECROSIS OR APOPTOSIS DEPENDING ON MITOCHONDRIAL-FUNCTION
    ANKARCRONA, M
    DYPBUKT, JM
    BONFOCO, E
    ZHIVOTOVSKY, B
    ORRENIUS, S
    LIPTON, SA
    NICOTERA, P
    [J]. NEURON, 1995, 15 (04) : 961 - 973
  • [3] Mitochondria, free radicals, and neurodegeneration
    Beal, MF
    [J]. CURRENT OPINION IN NEUROBIOLOGY, 1996, 6 (05) : 661 - 666
  • [4] Brorson JR, 1997, J NEUROCHEM, V68, P95
  • [5] Budd SL, 1996, J NEUROCHEM, V67, P2282
  • [6] CHOI DW, 1990, ANNU REV NEUROSCI, V13, P171, DOI 10.1146/annurev.neuro.13.1.171
  • [7] Du YS, 1997, J NEUROCHEM, V69, P1382
  • [8] Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons
    Du, YS
    Bales, KR
    Dodel, RC
    HamiltonByrd, E
    Horn, JW
    Czilli, DL
    Simmons, LK
    Ni, BH
    Paul, SM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (21) : 11657 - 11662
  • [9] Ferrante Robert J., 1997, P229
  • [10] Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons
    Hantraye, P
    Brouillet, E
    Ferrante, R
    Palfi, S
    Dolan, R
    Matthews, RT
    Beal, MF
    [J]. NATURE MEDICINE, 1996, 2 (09) : 1017 - 1021