Possible roles of JNK pathway in the regulation of hippocampal proenkephalin and immediate early gene expression induced by kainic acid

Mitogen-activated protein kinases (MAPKs) may play crucial roles in the kai nic acid (KA)-evoked excitotoxic effect and the regulation of transcription factors (e,g, c-Fos and c-Jun) in hippocampus, but their exact role in the regulation of KA-induced opioid peptides expression has not been well char acterized in vivo. Therefore, we examined possible involvement of the phosp horylated form of JNK, as well as CREB, in the regulation of KA-induced pro enkephalin and immediate early genes (IEGs) expression in the rat hippocamp us, KA increased proenkephalin mRNA expression in rat hippocampus, which wa s decreased by pre-administration with cycloheximide (CHX, a protein synthe sis inhibitor). KA alone increased c-fos as well as c-jun mRNA levels. CHX further enhanced KA-induced c-fos and c-jun mRNA levels. Additionally, KA i ncreased the phosphorylation of JNK, especially JNK1, which was attenuated by CHX, CHX decreased KA-induced c-Fos protein expression. Interestingly, C HX itself increased the phosphorylation of CREB, which was abolished by KA administration. Our results suggest that the phosphorylation of JNK is invo lved in the up-regulation of the proenkephalin gene expression via c-Fos an d c-Jun that is induced by KA in rat hippocampus. However, the phosphorylat ion of CREB is not associated with the up-regulation of the proenkephalin m RNA level induced by KA in the rat hippocampus.