PEPTIDE INHIBITORS OF CASPASE-3-LIKE PROTEASES ATTENUATE 1-METHYL-4-PHENYLPYRIDINUM-INDUCED TOXICITY OF CULTURED FETAL-RAT MESENCEPHALIC DOPAMINE NEURONS

Multiple aspartate-specific cysteine proteases have been identified an d specific members of this family have been implicated in the apoptoti c death of many mammalian cell types. Caspase-3-like proteases seem to play a pivotal role in neuronal apoptosis since mice with germline in activation of the caspase-3 gene manifest profound alterations in neur ogenesis. Moreover, inhibitors of caspase-3-related proteases have bee n 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 conta ining dopamine neurons. We demonstrate that low concentrations of 1-me thyl-4-phenylpyridinium induce apoptosis in dopamine neurons by morpho logical and biochemical criteria. Moreover, pretreatment of ventral me sencephalon 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-phenylpyr idinium, whereas the caspase-1-like inhibitor Ac-YVAD-CHO was without effect. Our data indicate that exposure of cultured ventral mesencepha lon dopamine neurons to low concentrations of 1-methyl-4-phenylpyridin ium results in apoptotic death and that caspase-3-like proteases may m ediate the neurotoxic apoptotic actions of 1-methyl-4-phenylpyridinium . (C) 1998 IBRO, Published by Elsevier Science Ltd.