Effect of melatonin on the regulation of proenkephalin and prodynorphin mRNA levels induced by kainic acid in the rat hippocampus

The in vivo short-term effect of melatonin on kainic acid (KA)-induced proenkephalin (proENK) or prodynorphin (proDYN) mRNA, and on AP-1 protein levels in the rat hippocampus, were studied. Melatonin (5 mg/kg) or saline was administered intraperitoneally (i.p.) to rats 30 min prior to and immediately after i.p. injection of KA (10 mg/kg). Rats were sacrificed 1 and 3 h after KA injection. The proENK and proDYN mRNA levels were significantly increased 3 h after KA administration. The elevations of both proENK and proDYN mRNA levels induced by KA were significantly inhibited by the preadministration with melatonin. The increases of proENK and proDYN mRNA levels induced by KA were well-correlated with the increases of c-Fos, Fra-2, FosB, c-Jun, and JunB protein levels, which were significantly increased 3 h after KA administration and effectively inhibited by administration with melatonin. In an electrophoretic mobility shift assay, both AP-1 and ENKCRE-2 DNA binding activities were increased by KA, which were also attenuated by the administration of melatonin. In addition, cross-competition studies revealed that AP-1 or ENKCRE-2 DNA binding activity was effectively reduced by the 50x unlabeled cross-competitor. Therefore, these data suggest that melatonin has an inhibitory role in KA-induced gene expression, such as proENK and proDYN mRNA expression, and this may be due to a reduction of KA-induced AP-1 or ENKCRE-2 DNA binding activity.