Peptide inhibitors of caspase-3-like proteases attenuate 1-methyl-4- phenylpyridinum-induced toxicity of cultured fetal rat mesencephalic dopamine neurons

R. C. Dodel, Y. Du, K. R. Bales, Z. D. Ling, P. M. Carvey, S. M. Paul

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

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 protease 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-methyl-4-phenylpyridinium using ventral mesencephalon cultures containing dopamine neurons. We demonstrate that low concentrations of 1-methyl-4-phenylpyridinium 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 induced by low concentrations of 1-methyl-4- phenylpyridinium, whereas the caspase-1-like inhibitor Ac-YVAD-CHO was without effect. Our data indicate that exposure of cultured ventral mesencephalon dopamine neurons to low concentrations of 1-methyl-4- phenylpyridinium results in apoptotic death and that caspase-3-like proteases may mediate the neurotoxic apoptotic actions of 1-methyl-4-phenylpyridinium.

Original languageEnglish (US)
Pages (from-to)701-707
Number of pages7
JournalNeuroscience
Volume86
Issue number3
DOIs
StatePublished - Jun 8 1998

Keywords

  • 1-methyl-4-phenylpyridinium
  • Apoptosis
  • Cysteine proteases
  • Neuron
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)

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