Brain regional pharmacokinetics of hydroxytyrosol and its molecular mechanism against depression assessed by multi-omics approaches

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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