Peptide inhibitors of caspase-3-like proteases attenuate MPP + -induced toxicity of cultured fetal rat mesencephalic dopamine neurons
Multiple aspartate-specific cysteine proteases have been identified and specific members of this family have been implicated in the apoptotic death of many mammalian cell types. Caspase-3-like proteases seem to play a pivotal role in neuronal apoptosis since mice with germline inactivation of the ca...
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Published in | Neuroscience Vol. 86; no. 3; pp. 701 - 707 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Ltd
01.06.1998
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Subjects | |
Online Access | Get full text |
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Summary: | Multiple aspartate-specific cysteine proteases have been identified and specific members of this family have been implicated in the apoptotic death of many mammalian cell types. Caspase-3-like proteases seem to play a pivotal role in neuronal apoptosis since mice with germline inactivation of the caspase-3 gene manifest profound alterations in neurogenesis. Moreover, inhibitors of caspase-3-related proteases have been shown to inhibit neuronal apoptosis. Here we extend recent work from our laboratory on the mechanisms mediating the neurotoxic actions of 1-phenyl-4-methylpyridinium using ventral mesencephalon cultures containing dopamine neurons. We demonstrate that low concentrations of 1-phenyl-4-methylpyridinium induce apoptosis in dopamine neurons by morphological and biochemical criteria. Moreover, pretreatment of ventral mesencephalon cultures with the tetrapeptide inhibitors of the caspase-3-like proteases; zVAD-FMK or Ac-DEVD-CHO specifically inhibit death of dopamine neurons neurons induced by low concentrations of 1-phenyl-4-methylpyridinium, whereas the caspase-1-like inhibitor Ac-YVAD-CHO was without effect. Our data indicate that exposure of cultured ventral mesencephalondopamine neurons to low concentrations of 1-phenyl-4-methylpyridinium results in apoptotic death and that caspase-3-like proteases may mediate the neurotoxic apoptotic actions of 1-phenyl-4-methylpyridinium. |
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ISSN: | 0306-4522 1873-7544 |
DOI: | 10.1016/S0306-4522(98)00154-7 |