Novel ginkgolide B derivative attenuated the function and expression of P-glycoprotein at the blood–brain barrier, presenting brain-targeting ability

A series of ginkgolide B derivatives (GBD) were designed for delivery of ginkgolide B (GB) across the blood–brain barrier to the brain. Three GBD had shown considerable brain-targeting ability in our previous study. Among them, the ginkgolide B pyrazine (PGB) derivative was selected as a promising novel GB derivative because of its highest brain distribution. Further investigations with regard to PGB and GB's effects on inhibiting the expression of P-gp and attenuating the efflux function of P-gp were reported in this study. They were considered a big step towards better understanding the relationship between GBD's brain-targeting behavior and P-gp regulation. Western blot analysis indicated that PGB was more effective in inhibiting the expression of P-gp than GB in rat brain microvessel endothelial cells (rBMECs) and rat cerebral cortexes and hippocampus. Moreover, the efflux function of P-gp via the transportation of rhodamine 123 was significantly inhibited in PGB-treated rat brains. Preventive medication with PGB induced a better protection of the integrity of the BBB in incomplete ischemia mice. Our findings revealed that an attenuated expression level and efflux function of P-gp and improved protective effect could be realized by the ginkgolide B derivative. These investigations will pave the way for designing more efficient brain-targeting derivatives of ginkgolide and some other central nervous system drugs.