Studies have implicated the c-jun N-terminal kinase (JNK) pathway in mediating programmed cell death in neurons. We have previously demonstrated that the protein expression of c-jun and PO4-c-jun is increased in the substantia nigra (SN) following induction of apoptosis by striatal target lesion or by injection of the neurotoxin 6-hydroxydopamine (6OHDA). Nuclear expression of PO4-c-jun is observed in conjunction with apoptotic chromatin clumps in dopamine (DA) neurons suggesting that the JNK pathway may play a role in apoptosis in these neurons. JNK signaling can be mediated through a number of upstream kinases, including the mixed lineage kinase (MLK) family. CEP-11004 is a novel inhibitor of this family and has been shown to attenuate MPTP-mediated elevation in PO4-JNK as well as DA neuronal death (McKenna et al, SFN '01). We have therefore used CEP-11004 to assess the functional role of the MLKs in apoptosis induced in the SN by 6OHDA. CEP-11004 at a dose of 1 mg/kg sc was administered daily from the d...