Dipeptidyl peptidase-4 inhibitors enhance memory retention via neuropeptide Y

We have previously shown that neuropeptide Y (NPY) prolongs the retention of memory in the object discrimination test in mice. In this study, we investigated the potential memory-enhancing effects of dipeptidyl peptidase-4 (DPP4) inhibitors, commonly referred to as gliptins, which are known to prevent the degradation of NPY, thereby increasing its concentration. We show that administration of sitagliptin (50 and 100 mg/kg/day) and linagliptin (5 and 10 mg/kg/day) via the drinking water facilitates the retention of object memory in male CD1 mice, extending memory retention to time points when control mice no longer retain memory. Similar to gliptin-treated mice, male and female homozygous and heterozygous DPP4 deficient mice displayed intact object memory at time points when wild-type littermates showed no memory. Sitagliptin treatment, however, did not facilitate the retention of memory in male and female homozygous NPY deficient mice, indicating that NPY is essential for the memory-enhancing effects of sitagliptin. These results indicate that sitagliptin exerts memory-enhancing effects through an NPY-dependent mechanism and highlight the potential of gliptins as cognitive enhancers in healthy individuals.