Targeting neuroinflammation by hydroxytyrosol-A as a strategy for safer
anti-depressant drug development
Abstract
Chronic depression is a complex disorder with huge societal
repercussions. Although currently used antidepressant drugs are
generally effective, most of these drugs display serious adverse
effects. Moreover, the incompletely elucidated pathological mechanisms
of depression constitutes a bottleneck in development of
antidepressants. Among them, the field targeting neuroinflammation,
which is associated with depression, remains unexplored. Here, we
evaluated neuroprotective and antidepressant properties of a phenolic
phytochemical, hydroxytyrosol (HT). We observed that HT treatment
alleviated depressive-like behaviors in rodent models of learned
helplessness (LH), chronic restraint stress (CRS) and chronic
unpredictable mild stress (CUMS). HT improved hippocampal neuronal
injury with modulation of microglia activation, inflammatory cytokines
production, mitochondrial damage and BDNF signaling pathway, as well as
the cellular level. In addition, targeted metabolomics results showed
that HT compensated for the neurotransmitters deficiency and inhibited
the tryptophan-kynurenine metabolism in the brain of CUMS rats. RNA-Seq
studies confirmed that the antidepressant effect of HT was modulated by
BDNF signaling pathways closely associated with the functions of nerve
fibers, myelin formation, microglia differentiation, and nerve
regeneration. There is potential for developing neuroprotective agents
based on HT to treat depression disorders caused by inflammation-related
neuronal injury.