Tetrahydrocurcumin ameliorates depression-like behaviors in chronic restraint stress mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF-κB pathwayOA

Objective To investigate whether tetrahydrocurcumin(THC)ameliorates depression-like behaviors in mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF‑κB pathway.Methods A mouse model of depression was established using chronic restraint stress(CRS).The mice were treated with THC(2.5,5,or 10 mg/k)or sertraline(10 mg/kg)on a daily basis for 21 consecutive days.Anxiety-and depression-like behaviors of the mice were assessed using open field,elevated plus maze,tail suspension,and forced swimming tests.Serum levels and hippocampal expression levels of SIRT1,p-NF-κB/NF-κB,inflammatory factors(TNF-αand iNOS),and neurotrophic factors(BDNF,GDNF,and TGF-β1)were measured using ELISA,Western blotting,or immunohistochemistry.The expression levels of hippocampal CA3 microglial activation marker(Iba1)and silent information regulator 1(SIRT1)were analyzed using immunofluorescence staining.In the in vitro experiment,BV2 microglial cells were stimulated with lipopolysaccharide(LPS)and treated with THC with or without the SIRT1 inhibitor EX-527 for validating the pathway mediating the effect of THC.Results THC treatment significantly alleviated CRS-induced anxiety-and depression-like behaviors and increased body weight gain of the mice.THC obviously reduced serum and hippocampal levels of TNF-αand iNOS,increased the expression levels of SIRT1,BDNF,GDNF,and TGF-β1,and inhibited NF‑κB activation in the hippocampus.The THC-treated mice showed significantly reduced Iba1 expression and Iba1^(+)/SIRT1^(+)cells and increased SIRT1 expression in the hippocampal CA3 region.In cultured BV2 cells,THC effectively attenuated LPS-induced NF-κB activation,lowered expressions of TNF-αand iNOS,and promoted SIRT1,BDNF,GDNF,and TGF-β1 expressions;these effects were obviously blocked by treatment with EX-527,confirming SIRT1 dependence of the effect of THC.Conclusion THC produces significant antidepressant-like effects in CRS mice likely by activating SIRT1 to suppress NF‑κB-mediated neuroinflammation and restore neurotrophic factor expressions.These findings highlight the SIRT1/NF-κB pathway as a key mechanism mediating the therapeutic effect of THC against depression.