Hydroxytyrosol is potential against depression

Depression is the greatest cause of disability worldwide. According to the World Health Organisation (WHO), depression affects approximately 264 million people of all ages worldwide. Although depression may afflict people of either gender, studies consistently show that women are more prone than males to suffer it.


Hydroxytyrosol (HT) is mostly found in olive leaves following oleuropein hydrolysis. Other than its antioxidant, cardioprotective, anti-inflammatory, antibacterial, and neuroprotective characteristics, it has shown anti-depressive activity as the major chemical in olive leaves due to its possible capacity to penetrate the blood-brain barrier (BBB). Our prior investigation found that HT has beneficial antidepressant action as well. However, little information on the brain regional absorption of HT is available, and the underlying antidepressant mechanism is unknown.


According to a recent study, BBB permeability studies in normal and chronic unpredictable mild stress (CUMS)-mice indicated that enhanced BBB permeability in CUMS mice was caused by tight junction-related protein shortage. According to the established LC-MS/MS method, it was discovered that HT could not be detected in large quantities in the cerebrospinal fluids and brains of normal mice after oral administration, whereas it could penetrate the BBB (200-fold higher) and was mostly distributed in the hippocampus of CUMS mice. Meanwhile, in CUMS mice, multi-omics analysis paired with focused analysis revealed that HT might primarily increase fatty acid production and metabolism in the hippocampus with region-specific responses and associated suppression of the C3-CD11b pathway. Furthermore, in vitro investigations verified HT's anti-complement capacity, which may suppress the C3-CD11b pathway and alleviate LPS-induced BV-2 microglia activation.


According to the findings of this study, HT can excessively penetrate the BBB and be mostly distributed in the hippocampus of depressive mice, thereby improving fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of the C3-CD11b pathway for microglia activation. These findings provide a better knowledge of the brain regional pharmacokinetics of HT as well as its associated molecular mechanism against depression.