Effect of pipernonaline from Piper retrofractum on memory disorder in mice and neurite outgrowth activity of PC12 cells.

In this study, we discovered compounds comprising a piperidine skeleton in Piper retrofractum; the compounds exhibit PC12 dendrite elongation activity. Furthermore, we examined the structure-activity relationship by comparing the activities of the isolated compounds 1, 3-7. Among the isolated compounds, two alkaloids (6 and 7) displayed significant neurite outgrowth (NOG) effects in the presence of 5 ng/mL nerve growth factor (NGF) in a dose-dependent manner. Comparison of the activity of 3 (Pipercide; 1.8% NOG positive at 100 µM), 6 (Dehydropipernonaline; 21.1% NOG positive at 100 µM), and 7 (Pipernonaline; 24.3% NOG positive at 100 µM) (Nobiletin; 25.4% at 50 µM as positive control) demonstrated that the piperidine skeleton is key to NOG activity. Furthermore, the carbon chain length and number of double bonds influence NOG activity. Moreover, the Barnes maze test showed that oral administration of compound 7 in mice improved memory disorders induced by scopolamine and corticosterone. These results provide extremely valuable foundational knowledge for elucidating the cognitive function-improving effects of P. retrofractum, a food spice.