Abstract
Background:
Hydroxytyrosol (HT), as the main compound in olive leaves with its potential ability to cross blood-brain barrier (BBB), has exhibited the advantaged antidepressant effect. However, no information is available regarding the brain regional uptake of HT, as well the underlying antidepressant mechanism remains unclear.
Purpose:
To comprehensively reveal the brain uptake of HT and its specific mechanism on the accompanying antidepressant activity.
Study design and methods:
The BBB penetration and brain regional distribution of HT in the normal and chronic unpredictable mild stress (CUMS)-induced depressive mice in consideration with the BBB integrality were analyzed. Then, the hippocampal region-specific responses of biomolecules and concurrent alterations in the therapeutic effect of HT on depression were explored using untargeted metabolomics, spatial-resolved metabolomics and tissue proteomics, which were confirmed by LPS-induced BV-2 microglia and CUMS mice.
Results:
BBB permeability analysis in normal and CUMS mice confirmed that increased BBB permeability of CUMS mice was induced by the deficiency of tight junction-related proteins. Consistently, according to the established LC-MS/MS method, it was found that HT could not be largely detected in the cerebrospinal fluids and brains of normal mice after oral administration, while it could excessively penetrate the BBB (200-fold higher), and mostly distributed in the hippocampus of CUMS mice. Meanwhile, multi-omics analysis combined with targeted analysis discovered that HT could mainly improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway in CUMS mice. Besides, in vitro experiments further confirmed the anti-complement ability of HT, which could inhibit C3-CD11b pathway for alleviating the LPS-induced BV-2 microglia activation.
Conclusion:
HT can excessively penetrate the BBB and be mostly distributed in the hippocampus of depressive mice, which contribute to improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway for microglia activation. These findings give the clearer understanding of brain regional pharmacokinetics of HT and its accompanying molecular mechanism against depression.
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