Neurite outgrowth-promoting furanocoumarins isolated from sudachi juice in PC12 cells

Sudachi (Citrus sudachi, a citrus fruit of the Rutaceae family) juice was found to promote neurite outgrowth in PC12 cells. Activity-guided purification of the juice led to the isolation of two furanocoumarins, byakangelicin and isopimpinellin, and a flavone, demethoxysudachitin, identifying them as neurite-outgrowth promoters for the first time. Byakangelicin and isopimpinellin showed markedly stronger neurite outgrowth-promoting activity than demethoxysudachitin, prompting a comparative evaluation of five furanocoumarins, including both isolated and related reference compounds. The results showed that the basic furanocoumarin scaffold alone is inactive, whereas substitution at either the C5 or C8 position of a furanocoumarin confers prominent activity, with dual substitution further improving the activity. Among the tested compounds, byakangelicin and isopimpinellin exhibited the most potent neurite outgrowth-promoting activity. These findings identify sudachi-derived furanocoumarins as previously unrecognized neurite-outgrowth promoters and suggest their potential as neurotrophic agents for supporting cognitive function.