It is well documented that the
mitogen-activated protein kinase pathway plays a pivotal role in rats with
6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrostriatal system. Our recent studies have shown that
mixed-lineage kinase 3 (MLK3) and apoptosis-inducing
kinase 1 (ASK1) are all involved in neuronal cell death induced by
ischemia, which is mediated by the MLK3/c-Jun NH2-terminal
kinase 3 (JNK3) and ASK1/JNK signaling pathway. To investigate whether these pathways are correlated with 6-OHDA-induced lesion as well, we examined the phosphorylation of MLK3, ASK1, and JNK3 in
6-OHDA rats. The results showed that both MLK3 and ASK1 could activate JNK3 and then subsequently enhance the neuronal death through its downstream pathways (i.e., nuclear and non-nuclear pathway).
K252a have wide-range effects including Trk inhibition, MLK3 inhibition, and activation of
phosphatidylinositol 3 kinase and
mitogen-activated protein kinase kinase signaling pathways through interactions with distinct targets and is a well known neuroprotective compound. We found that
K252a could protect dopaminergic neurons against cell program death induced by
6-OHDA lesion, and the phenotypes of
6-OHDA rat model treated with
K252a were partial rescued. The inhibition of
K252a on the activation of MLK3/JNK3 and ASK1/JNK3 provided a link between
6-OHDA lesion and stress-activated
kinases. It suggested that both proapoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play an important role in dopaminergic neuronal death in
6-OHDA insult. Thus, the JNK3 signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of
Parkinson disease, and
K252a may serve as a potential and important
neuroprotectant in therapeutic aspect in
Parkinson disease.