Received for publication June 6, 2007.
Revised September 7, 2007.
Accepted for publication September 11, 2007.

K252a prevents nigral dopaminergic cell death induced by 6-OHDA through inhibition of both MLK3/JNK3 and ASK1/JNK3 signaling pathways

Abstract

Abstract It is well documented that mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in rats with 6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrastriatal system. Our recent studies have shown that mixed-lineage kinase 3 (MLK3) and apoptosis-inducing kinase1 (ASK1) are all involved in neuronal cell death induced by ischemia, which is mediated by the MLK3/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 PI3K and MEK 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 pro-apoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play 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.

Key words: Dopamine, Phosphorylation/Dephosphorylation, MAP Kinase, Jun Kinase, Immunocytochemistry, Structure/function/mechanism, Apoptosis, Mechanisms of cell killing/apoptosis