Peptide inhibitors of caspase-3-like proteases attenuate MPP + -induced toxicity of cultured fetal rat mesencephalic dopamine neurons

• Published in: Neuroscience Vol. 86; no. 3; pp. 701 - 707
• Main Authors: Dodel, R.C, Du, Y, Bales, K.R, Ling, Z.-D, Carvey, P.M, Paul, S.M
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.06.1998
• Subjects: DA, dopamine; MPP +, 1-methyl-4-phenylpyridinium; TH, tyrosine hydroxylase; TH-ir, TH-immunoreactive; VM, ventral mesencephalon; CGN, cerebellar granule neurons; DAPI, 4′,6′-diamidino-2-phenylindole
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00154-7

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.