title: Assessment of the Blood-Brain Barrier Permeability of Potential Neuroprotective Aurones in Parallel Artificial Membrane Permeability Assay and Porcine Brain Endothelial Cell Models.
abstract: Previously, several aurone derivatives were identified with promising neuroprotective activities. In developing these compounds to target the central nervous system (CNS), an assessment of their blood-brain barrier (BBB) permeability was performed using in vitro BBB models: parallel artificial membrane permeability assay-BBB which measures passive permeability and primary porcine brain endothelial cell model which enables determination of the involvement of active transport mechanism. Parallel artificial membrane permeability assay-BBB identified most compounds with high passive permeability, with 3 aurones having exceptional Pevalues highlighting the importance of basic amine moieties and optimal lipophilicity for good passive permeability. Bidirectional permeability assays with porcine brain endothelial cell showed a significant net influx permeation of the aurones indicating a facilitated uptake mechanism in contrast to donepezil, a CNS drug included in the evaluation which only displayed passive permeation. From pH-dependent permeability assay coupled with data analysis using pCEL-X software, intrinsic transcellular permeability (Po) of a representative aurone 4-3 was determined, considering factors such as the aqueous boundary layer that may hinder accurate in vitro to in vivo correlation. The Povalue determined supported the in vivo feasibility of the aurone as a CNS-active compound.
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Kok-Fui
authors.initials: KF
authors.lastname: Liew
authors.affiliation: Centre for Drug Research, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Nur Aziah
authors.initials: NA
authors.lastname: Hanapi
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Kit-Lam
authors.initials: KL
authors.lastname: Chan
authors.affiliation: Centre for Drug Research, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Siti R
authors.initials: SR
authors.lastname: Yusof
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia. Electronic address: chongyew@usm.my.
authors.forename: Chong-Yew
authors.initials: CY
authors.lastname: Lee
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D008567:Membranes, Artificial; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D013552:Swine
chemical_list: D001572:Benzofurans; D008567:Membranes, Artificial; D018696:Neuroprotective Agents; C486837:aurone
keywords: CNS; blood-brain barrier; drug design; drug-like properties; in vitro models; permeability