Discovery of a Neuroprotective Diosgenin Derivative as a Novel Antidepressant Candidate Targeting LPS-TLR4 Signaling

Depression is a widespread and increasing mental disorder,
yet
current antidepressants, including tricyclic antidepressants (TCAs)
and selective serotonin reuptake inhibitors (SSRIs), often cause notable
side effects and limited efficacy. Hence, safer therapeutic options
are needed. Diosgenin, a phytosteroid sapogenin from the Dioscoreaceae
plants, has demonstrated therapeutic potential for neurological disorders
but is hindered by unclear target mechanism, poor solubility, and
limited bioavailability. Here, we synthesized diosgenin derivatives
and evaluated their biological activities. Among them, compound 8 exhibited the highest therapeutic index (TI = 19.8), strongly
inhibiting LPS-induced NO production with minimal cytotoxicity. Compound 8 suppressed proinflammatory gene expression, showed neuroprotective
effects in vitro, ameliorated LPS-induced reactive
astrogliosis and microgliosis in vivo, and alleviated
LPS-induced depressive-like behaviors in mice. Computational docking
and centrifugal ultrafiltration assays identified LY96 as a potential
target, suggesting modulation of LPS-TLR4 signaling. Collectively,
these findings indicate that compound 8 holds promise
as a safer antidepressant candidate.