Abstract
Embelin is well-known in ethnomedicine and reported to have central nervous system activities. However, there is no report on blood-brain barrier (BBB) permeability of embelin. Here the BBB permeability of embelin was evaluated using in vitro primary porcine brain endothelial cell (PBEC) model of the BBB. Embelin was also evaluated for acetylcholinesterase (AChE) inhibitory activity and docking prediction for interaction with AChE and amyloid beta (Aβ) binding sites. Embelin was found to be non-toxic to the PBECs and did not disturb the PBEC barrier function. The PBECs showed restrictive tight junctions with average transendothelial electrical resistance of 365.37 ± 113.00 Ω.cm2, for monolayers used for permeability assays. Permeability assays were conducted from apical-to-basolateral direction (blood-to-brain side). Embelin showed apparent permeability (Papp) value of 35.46 ± 20.33 × 10−6 cm/s with 85.53% recovery. In vitro AChE inhibitory assay demonstrated that embelin could inhibit the enzyme. Molecular docking study showed that embelin binds well to active site of AChE with CDOCKER interaction energy of −65.75 kcal/mol which correlates with the in vitro results. Docking of embelin with Aβ peptides also revealed the promising binding with low CDOCKER interaction energy. Thus, findings from this study indicate that embelin could be a suitable molecule to be further developed as therapeutic molecule to treat neurological disorders particularly Alzheimer's disease.
Highlights
The blood brain barrier (BBB) is highly selective interface that separates the central nervous system (CNS) from the bloodstream (Clark, 2003; Abbott et al, 2010)
Tight junctions integrity of the porcine brain endothelial cells (PBECs) monolayer was determined by measuring the transendothelial electrical resistance (TEER) at 1 min interval up to 30 min, the cells returned to the incubator, followed by measurement of TEER at minute 60
Embelin was tested at 30 μg/mL, Dulbecco’s modified Eagle’s medium (DMEM) and dimethyl sulfoxide (DMSO) were used as negative and positive control respectively
Summary
The blood brain barrier (BBB) is highly selective interface that separates the central nervous system (CNS) from the bloodstream (Clark, 2003; Abbott et al, 2010). The endothelium facilitates and regulates substance entry between the blood and the CNS, as well as protecting the brain from harmful toxins and pathogens. The protective nature of the BBB becomes a disadvantage as it restricts the entry of many potential therapeutic agents (Czupalla et al, 2014). Developed drugs targeting CNS disorders have the poorest success rate and often failed in the clinical trial (FernándezRuiz, 2018). Around 98% of the potential drugs do not cross the BBB. It is very crucial to know whether a compound can cross the BBB and utilize this information during drug development before proceeding to clinical trial
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