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

doi:10.12122/j.issn.1673-4254.2026.08.01

Abstract

Abstract:

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-α and 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-α and 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-α and 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.

Key words: depression, chronic restraint stress, tetrahydrocurcumin, silent information regulator 1, nuclear factor kappa-B, neuroinflammation, neurotrophy

Tengteng MA, Jianyu YANG, Yun YUAN, Haiyun LUO, Yubin WEI, Jingyuan MENG, Xingping WANG, Jianping XIE, Ying GUO. Tetrahydrocurcumin ameliorates depression-like behaviors in chronic restraint stress mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF-κB pathway[J]. Journal of Southern Medical University, 2026, 46(8): 1719-1729.

Figures/Tables 6

Fig.1 Effects of tetrahydrocurcumin (THC) on depression-like behaviors in mice with chronic restraint stress (CRS). A: Flowchart of the experiment protocol. B: Trajectory diagram of the mice in open field test (OFT). C: Trajectory diagram of the mice in elevated plus maze (EPM) test. D: Total distance traveled of the mice in OFT. E: Percentage of distance traveled in center in OFT. F: Percentage of time in the center in OFT. G: Percentage of distance in the center in EPM test. H: Percentage of time in the center in EPM test. I: Percentage of immobility time in tail suspension test. J: Percentage of immobility time in forced swimming test. K: Growth rate of body mass. Data are presented as Mean±SE (n=10). *P<0.05, **P<0.01 vs control; #P<0.05, ##P<0.01 vs CRS.

Fig.2 Serum levels of SIRT1, TNF-α, iNOS, BDNF, GDNF and TGF-β1 in CRS mice receiving treatment with low, medium, and high doses of THC (THC-L, THC-M and THC-H groups, respectively). A: Serum levels of SIRT1. B: Serum levels of TNF-α. C: Serum levels of iNOS. D: Serum levels of BDNF. E: Serum levels of GDNF. F: Serum levels of TGF-β1. Data are presented as Mean±SE (n=4). **P<0.01 vs control group; #P<0.05, ##P<0.01 vs CRS group.

Fig.3 Effects of different doses of THC on protein expressions of SIRT1, p-NFκB/NFκB, TNF-α, iNOS, BDNF, GDNF and TGF-β1 in the hippocampus of CRS mice detected by Western blotting. A-G: Western blotting for detecting the expression levels of SIRT1, p-NFκB/NFκB, TNF-α, iNOS, BDNF and GDNF. H-I: Western blotting for detecting the expression levels of TGF-β1. Data are presented as Mean±SE (n=4). **P<0.01 vs control group; #P<0.05, ##P<0.01 vs CRS group.

Fig.4 Effects of THC on protein expressions of SIRT1, TNF-α, iNOS, BDNF, GDNF and TGF-β1 in the CA1, CA2, CA3, and DG regions of the hippocampus in CRS mice detected by immunohistochemical staining (Original magnification: ×400). A-E: Expression levels of SIRT1 in the CA1, CA2, CA3, and DG regions. F-J: Expression levels of TNF-α in the CA1, CA2, CA3, and DG regions. K-O: Expression levels of iNOS in the CA1, CA2, CA3, and DG regions. P-T: Expression levels of BDNF in the CA1, CA2, CA3, and DG regions. U-Y: Expression levels of GDNF in the CA1, CA2, CA3, and DG regions. Z-AD: Expression levels of TGF-β1 in the CA1, CA2, CA3, and DG regions. Data are presented as Mean±SE (n=3). **P<0.01 vs control group; ##P<0.01 vs CRS group.

Fig.5 Effects of THC on protein expressions of Iba1, SIRT1, and Iba1+/SIRT1+ in the CA3 region of the hippocampus in CRS mice detected by immunofluorescence staining (×400). A: Immunofluorescence staining images of the CA3 region for detecting expressions of Iba1, SIRT1, and Iba1+/SIRT1+ in different groups. B-D: Quantitative analysis of Iba1, SIRT1, and Iba1+/SIRT1+expressions (Mean±SE, n=3). **P<0.01 vs control group; ##P<0.01 vs CRS group.

Fig.6 Effects of THC on protein expressions of SIRT1, p-NFκB/NFκB, TNF-α, iNOS, BDNF, GDNF and TGF-β1 in BV2 microgliall cells induced by LPS. A-G: Western blotting for detecting the expression levels of SIRT1, p-NFκB/NFκB, TNF-α, iNOS, BDNF and GDNF. H-I: Western blotting for detecting the expression levels of TGF-β1. J-K: Immunofluorescence staining for detecting the expression levels of TNF-α (×400). Data are presented as Mean±SE (n=3). *P<0.05, **P<0.01.

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