Abstract
As the number of central nervous system (CNS) drug candidates is constantly growing, there is a strong need for precise a priori prediction of whether an administered compound is able to cross the blood–brain barrier (BBB). The aim of this study was to evaluate the ability to cross the BBB of triterpenoid saponins occurring in Astragalus mongholicus roots. The research was carried out using in silico methods combined with postmortem studies on the brain tissues of mice treated with isolated astragaloside IV (AIV). Firstly, to estimate the ability to cross the BBB by the tested saponins, new quantitative structure–activity relationship (QSAR) models were established. The reliability and predictability of the model based on the values of the blood–brain barrier penetration descriptor (logBB), the difference between the n-octanol/water and cyclohexane/water logP (ΔlogP), the logarithm of n-octanol/water partition coefficient (logPow), and the excess molar refraction (E) were both confirmed using the applicability domain (AD). The critical leverage value h* was found to be 0.128. The relationships between the standardized residuals and the leverages were investigated here. The application of an in vitro acetylcholinesterase-inhibition test showed that AIV can be recognized as the strongest inhibitor among the tested compounds. Therefore, it was isolated for the postmortem studies on brain tissues and blood using semi-preparative HPLC with the mobile phase composed of water, methanol, and ethyl acetate (1.7:2.1:16.2 v/v/v). The results of the postmortem studies on the brain tissues show a regular dependence of the final concentration of AIV in the analyzed brain samples of animals treated with 12.5 and 25 mg/kg b.w. of AIV (0.00012299 and 0.0002306 mg, respectively, per one brain). Moreover, the AIV logBB value was experimentally determined and found to be equal to 0.49 ± 0.03.
Highlights
The blood–brain barrier (BBB) term is used to describe the unique properties of the microvasculature of the central nervous system (CNS) [1]
The predictive potency of newly constructed quantitative structure–activity relationship (QSAR) models was estimated by the leave-ten-out (LTO) cross-validation procedure
The QSAR models were based on the multiple linear regression (MLR) methodology with the backward elimination of variables in order to limit the differences between the actual and the estimated BBB values
Summary
The blood–brain barrier (BBB) term is used to describe the unique properties of the microvasculature of the central nervous system (CNS) [1]. The endothelial cells of brain microvasculature are the anatomical components of the BBB. They form tight junctions, which, along with pericytes, astrocytes, oligodendrocytes, microglia, and neurons, construct the neurovascular unit [2]. Despite the protective nature of the blood–brain barrier on the CNS, the inability of substances to cross the BBB is a key factor that should be taken into account in the early stages of drug discovery processes [6]. The BBB is formed by endothelial cells that line cerebral microvessels [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
