Effect of Paracellular Permeability Increasing on Transport of Squamosamide Derivative FLZ Across the in vitro BBB Models under Parkinson's Disease Pathological

Abstract

Abstract: Objective To study the effect of paracellular permeability on the transport characteristics of squamosamide derivative FLZ across the physiological and Parkinson's disease (PD) pathological in vitro blood-brain barrier (BBB) models. Methods In vitro BBB models mimicking physiological and PD pathological-related BBB properties were constructed by C6 astroglial cells co-cultured with primary normal or PD rat cerebral microvessel endothelial cells (rCMECs) and in vitro permeability experiments of FLZ were carried out. The effects of P-gp inhibitor zosuquidar and increasing paracellular permeability on the in vitro permeability and efflux ratio of FLZ were also investigated. Results The transport of various concentrations of FLZ (1, 5, 10 μM) through the out of contact co-culture model and in contact co-culture model occurred in both A~B and B~A directions, and Papp B~A transport were significantly higher than those for A~B transport at each FLZ concentration. Upon specific blocking of P-gp using zosuquidar increased intracellular accumulation of FLZ both in the physiological and PD pathological in vitro BBB models and resulted in significantly reduced efflux ratio. Results also showed that more brain penetration of FLZ was detected in the PD pathological model compared to the physiological group with increasing paracellular permeability, but the alter of efflux ratio was not observed as P-glycoproteinon mediated FLZ efflux. Conclusion The poor brain penetration of FLZ are mainly due to the P-gp transport system in the BBB under physiological and PD pathological in vitro BBB models.

Key words: FLZ, blood-brain barrier, Parkinson's disease, paracellular, P-glycoprotein

CLC Number:

R965

LIU Qian, HOU Jin-feng, ZHANG Jin-lan, ZHANG Dan, BAO Xiu-qi, SUN Hua. Effect of Paracellular Permeability Increasing on Transport of Squamosamide Derivative FLZ Across the in vitro BBB Models under Parkinson's Disease Pathological[J]. Chinese Journal of Pharmacovigilance, 2018, 15(1): 6-11.

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