Transcriptional interruption of cAMP response element binding protein modulates superoxide dismutase and neuropeptide Y-mediated feeding behavior in freely moving rats

The appetite-suppressing effect of phenylpropanolamine (PPA) has been attributed to its inhibitory action on neuropeptide Y (NPY), an appetite stimulant. However, molecular mechanisms underlying this effect are not clear. This study aimed to investigate if cAMP response element binding protein (CREB) signaling was involved. Moreover, possible role of superoxide dismutase-2 (SOD-2) during PPA treatment was also examined. Rats were daily treated with PPA for 4 days. Changes in hypothalamic NPY, protein kinase A, CREB, and SOD-2 mRNA contents were measured and compared. Results showed that protein kinase A, CREB, and SOD-2 mRNA levels increased during PPA treatment, which is concomitant with decreases in NPY and feeding. Moreover, CREB DNA binding activity detected by electromobility shift assay increased during PPA treatment, revealing an involvement of CREB-dependent gene transcription. Furthermore, infusions of CREB antisense oligonucleotide (or missense control) into cerebroventricle were performed at 1 h before daily PPA treatment in free-moving rats, and results showed that CREB knockdown could block PPA-induced anorexia and modify NPY and SOD-2 mRNA content toward normal. It is suggested that CREB signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of NPY gene expression and that an increase of SOD-2 may favor this modulation.